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Memory T Cells in Transplantation: Old Challenges Define New Directions

Nicosia, Michael PhD1; Fairchild, Robert L. PhD1; Valujskikh, Anna PhD1

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doi: 10.1097/TP.0000000000003169
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Abstract

INTRODUCTION

During protective immune responses, T cell receptor (TCR) engagement with peptide:MHC complex on the surface of antigen-presenting cells causes extensive T cell expansion followed by effector functions and pathogen clearance. During the resolution of effector T cell (TEFF) responses, the antigen-specific T cell populations contract but leave behind a small subset of long-lived memory cells that are uniquely positioned and equipped for future host protection. Due to the same properties however, memory T cells with reactivity toward donor alloantigens undermine successful organ transplantation.

The obvious priming and accumulation of alloreactive memory T cells can occur via direct exposure to foreign MHCs during previous transplantations, blood transfusions, and pregnancies.1,2,3 In addition, alloreactive memory cells are generated as a result of heterologous immunity occurring when the peptides of commensal bacteria or environmental antigens presented on self-MHC mimic the molecular structure of alloantigens.4 In laboratory mice, which are raised in standard pathogen-free conditions,5 such endogenous memory T cells make up 0.05%–1.00% of the total T cell pool.6,7 In contrast, constant exposure to pathogens and infections in nonhuman primates (NHPs) and humans can lead to the acquisition of potent alloreactivity.8 Multiple studies demonstrated occurrences of cross-reactivity between individual pathogens and allo-MHC molecules. For instance, Adams et al showed that prior lymphocytic choriomeningitis virus infection of C57BL/6 mice induces alloreactive CD8 T cells that can subsequently reject skin allografts despite mixed chimerism-costimulatory blockade-based tolerance induction.9 Analogously, murine gammaherpesvirus 68 (MHV68) infection-induced heterologous immunity in C57BL/6 mice resulting in accelerated rejection of BALB/c skin allografts.10 Bacterial infections such as Leishmania major can also stimulate the generation of alloreactive T cells and worsen transplant outcomes in specific mouse strain combinations.11 Examples in humans have also been demonstrated such as HLA-B8+ patient sensitization to HLA-B44028,11 following Epstein-Barr virus infection.

Regardless of their origin, donor-reactive memory T cells are detrimental in the context of organ transplantation. Preexisting CD4 and CD8 memory T cells are rapidly reactivated and give rise to pathogenic effector subsets that can migrate into the graft and secrete proinflammatory cytokines or mediate cytotoxicity upon reactivation.12 Memory helper T cells provide efficient help for B cells to induce generation of donor-specific antibody (DSA) leading to antibody-mediated rejection.13,14,15 Animal studies demonstrated that within 24–48 hour posttransplant, CD4 and CD8 memory T cells infiltrate allografts where they exacerbate the effects of ischemia/reperfusion injury resulting in endothelial cell activation, intragraft chemokine production, and DAMPs release.16,17

Over the past 20 years, several subsets of memory T cells were defined based on the expression of adhesion molecules, chemokine, and cytokine receptors (Table 1). Initially memory T cells have been divided into CD62Lhi/CCR7hi central memory cells (TCM) and CD62Llo/CCR7lo effector memory T cells (TEM). Expression of CCR7 and CD62L in TCM facilitates homing from the blood into secondary lymphoid organs, while TEM can migrate from the blood to the peripheral tissues and are equipped to do so through increased expression of integrins and specific chemokine receptors.19 In the last decade, a specialized noncirculating, nonlymphoid tissue resident memory T cells (TRM) has been characterized.34,25 These localized cells provide antigen surveillance and rapid responses at sites of previous infections, especially at barrier sites such as skin, lung, intestine, and genitourinary tract.34

TABLE 1. - Memory T cell subsets and the surface markers used experimentally to define them
Subset Human markers Mouse markers Common markers References
Naïve CD45RAhi CD44lo CD62Lhi 18
CD45ROlo CCR7hi
CD28hi
Central memory (TCM) CD45RAlo CD44hi CD62Lhi 19,20,21,22
CD45ROhi
CCR7hi
CD28hi
Effector memory (TEM) CD45RAlo CD44hi CD62Llo 19,20,21,22
CD45ROhi CCR7lo
CD28hi
Terminally differentiated effector memory (TEMRA) CD45RAhi 22,23,24
CD45ROlo
CD62Llo
CCR7lo
CD28lo
CD57hi
KLRG1hi
Resident memory (TRM) CD45RAlo CD44hi CD62Llo 25,21,26
CD45ROhi CCR7lo
CD103hi
CD69hi
S1PR1lo
T follicular helper (TFH) CD4+ 27,28,29
CXCR5+
PD-1hi CD40
ICOS
IL-21
T peripheral helper (TPH) CD4+ 30
CXCR5
PD-1hi CD40
ICOS
IL-21
T memory stem cell (TSCM) SCA1 31,32,33
IL-2Rb
CXCR3
CD45RA+
CD62L+
CD58
CD11a
CD95
SCA1, stem cell antigen 1.

NEWLY EMERGING MEMORY T CELL SUBSETS

Tissue Resident Memory Cells

Highly specialized and heterogenous TRM cells are a recent addition to the family of T cell subsets. They are noncirculating, a property that is facilitated by the surface markers used to define them. While both CD4+ and CD8+ memory T cells make up TRM subsets, most of the current knowledge in the field is generated by studying CD8+ TRM cells. TRM cells are thought to develop from common memory precursors that are present among activated CD127hi KLRG T cells following infection.35 In the skin, these precursors enter the epidermis early after infection and slowly mature into TRM phenotype (Table 1) following infection resolution. Maturation results in elevated expression of CD69, an early activation marker that promotes tissue retention of TRM precursors by antagonizing the functions of S1PR1,36 a chemokine receptor mediating lymphocyte egress into circulation. This is accompanied by the reduction in the expression of other known facilitators of tissue egress, CCR7 and KLF2.37 CD69 upregulation precedes the expression of another TRM associated marker—CD103, an adhesion molecule of the integrin family.38 CD103 binds to E-cadherin expressed by epithelial cells and is commonly referred to as a universal TRM marker. However, parabiosis studies showed the presence of CD103 TRM cells in a number of tissues39,40,41,42 and distinct cytokine output by CD103+ and CD103 TRM cells.43 Another marker commonly associated with TRM is CD49a (Very Late Antigen-1)44 and yet there are subsets that do not express CD49a,45 highlighting the heterogeneity of TRM population. TGF-β was identified as a key cellular factor required for CD103 expression and the establishment of TRM in multiple tissues.46,47 While other cytokines including IL-33, TNF-α, and IFN-α/β have been shown to promote TRM phenotypes in vitro, their role in the development and differentiation of TRM cells in vivo remains to be established.48,49 The use of latest tools in genomics and proteomics established that the newly matured TRM cells assume a unique transcriptional profile. TRM maturation is dependent upon the activities of the transcription factors Hobit and Blimp-1, both of which are necessary for tissue residence in natural killer T cells and liver-resident natural killer cells in addition to TRM.50 The exact requirements for TRM survival are not fully understood. CD8 TRM down-regulate the receptors for IL-7 and IL-15,49,51,52 key mediators of T cell homeostasis supporting survival and proliferation, respectively.53 While TCM and TEM CD8 cells require IL-15 for maintenance,54 its role in TRM cells appears to be location dependent.55

The presence of TRM at the barrier sites enables an immediate detection and robust responses to previously encountered pathogens. Activation, proliferation and effector functions of circulating memory T cells require the drainage of peripheral antigens to the secondary lymphoid organs. This process requires time, allowing pathogen to amplify within the body. Not surprisingly, enhanced protection by TRM cells compared with circulating memory cells was demonstrated for skin infections with Herpes simplex virus and Vaccinia virus.34,51 The same is true of TRM cells at mucosal sites, common points of entry for many infectious agents such as influenza.56,57 Furthermore TRM cells can play an important role in the control of nonacute infections such as the reactivation of latent herpes simplex virus.58

Given rapid and robust TRM responses, it is likely not a coincidence that organs containing high numbers of passenger memory T cells such as lung and intestine demonstrate some of the poorest clinical outcomes and lowest rates of graft acceptance.59 Despite dramatic improvements in first-year posttransplant attrition, long-term survival rates for these organs haven’t improved since the 1980s.35 In the context of transplantation, TRM cells may come from 2 distinct sources—donor organ and recipient. It remains unclear whether donor-derived passenger leukocytes contribute to alloreactivity and rejection or are simply cleared by infiltrating recipient T cells. A recent report by de Leur et al60 addressed the composition of TRM in kidney transplants. All evaluated allografts revealed the presence of both CD103+ and CD103 TRM cells that were predominantly CD8+, and the origin of these cells dependent on time elapsed after transplantation. Grafts analyzed within 1 month posttransplant had a TRM population dominated by donor-derived TRM. Transplants analyzed at later time points predominantly contained recipient derived CD8+ TRM, with no detectable donor-derived TRM by 5 months posttransplant.60 One proposed theory is that certain signals generated during transplantation, such as those during ischemia reperfusion injury, trigger lymphocyte tissue egress. This has been shown in the recipients of intestinal grafts, who exhibit donor-derived T cells in circulation 7–8 weeks posttransplant.61 In addition to the potential donor antigen delivery to recipient secondary lymphoid organs, the presence of donor-derived TRM increased the risk of graft versus host disease in this study.61 Animals studies suggest that donor TRM cells can precipitate graft tissue injury through multiple mechanisms. In a murine cardiac allograft study, donor-derived TRM cells provided help through cognate interactions to recipient B cells, causing autoantibody generation and ultimately cardiac allograft vasculopathy, a major limiting factor for long term graft survival.62

There are however, conflicting reports that donor-derived TRM cells may confer a protective role in transplantation. Consistent with this scenario, irradiation of donor grafts in a rodent model of spontaneously accepted liver transplants results in allograft rejection.63 As posttransplant infection can often precipitate rejection, the presence of protective sentinel cells in the graft may be beneficial. A study from Snyder et al64 investigating TRM cells in human lung transplant patients showed that grafts with higher frequencies of donor-derived TRM cells experience fewer instances of primary graft dysfunction and acute cellular rejection in comparison to the grafts with fewer donor TRM cells. Such findings suggest that future therapies that aim to maintain donor-derived TRM cells and prevent their replacement by recipient-derived TRM cells may improve transplant outcome. However, considering incomplete and often controversial data on the role of TRM cells in graft injury versus protection, therapies targeting donor-derived TRM may be better suited to certain types of solid organs, and as such should be put on hold until the role of these cells is better understood.

Terminally Differentiated Effector Memory T Cells

Studies in humans further added a distinct subset of terminally differentiated effector memory T cells (TEMRA) that reexpress CD45RA surface marker typical of naïve T lymphocytes.20 TEMRA cells require less IL-2 for survival and maintenance, are highly cytotoxic,65 and produce high levels of IFNγ18 simultaneously with low proliferative capacity and increased sensitivity to apoptosis.66 Furthermore, TEMRA cells lack CCR7 expression67 and are predominantly CD8+.68,69 These cells have been shown to make up a larger population of the T cells in blood and lymphoid tissues with aging as the proportion of naïve T cells decrease.69 They are characterized as terminally differentiated effector cells high in IFNγ secretion,19 highly cytotoxic,65 and highly sensitive to apoptosis with a low proliferative capacity.66 As with many of populations described TEMRA cells demonstrate heterogeneity within their population, as a naïve-TEMRA intermediate subset has been identified as being CD27+CD28+/−, while late differentiated and highly cytotoxic TEMRA cells are CD27CD28.70

TEMRA cells have been the focus of several studies in renal disease and transplantation. Patients with end-stage renal disease show an increased frequency of CD8+ TEMRA cells, above the normal increase seen during aging.71 A 2012 study on kidney transplant recipients revealed that recipients that did not suffer any biopsy-proved acute rejection episodes within the first 2 years demonstrated elevated pretransplant frequencies of CD8+ TEMRA cells compared with those that did suffer rejection in that timeframe.72 However, patients with elevated TEMRA cell frequencies also had increased rates of cancer during immunosuppression, indicating a state of immune senescence. Kidney transplant recipients have expanded numbers of CD8+ TEMRA cells,73 yet despite stable long-term graft function, long term persistence of this expansion is associated with a 2-fold increased risk of graft dysfunction in these patients.74 Transplant therapies directly targeting TEMRA cells have yet to be developed but the effect of some preexisting therapies have been observed. A longitudinal study on the effects of Rituximab (αCD20 mAb) induction on T and B lymphocyte phenotype and function show stable counts and frequencies of TEMRA cells for up to 24 months post-transplant regardless of Rituximab or basiliximab (αCD25 mAb) induction.75 Given their association with poor long-term outcomes, targeting TEMRA cells may prove highly beneficial at extending allograft survival.

Memory T Follicular Helper Cells

Follicular T helper cells (TFH) are a subset specialized in providing help to cognate B cells within the lymphoid follicles via expression of CD40, ICOS, IL-21, IL-4 and other molecules.27,76 The characteristic markers of this subset are a transcription factor Bcl6 and a chemokine receptor CXCR5 that is critical for recruitment and retention within lymphoid follicles. In the last decade, studies have shown how T cell memory and TFH cells intersect.28 Following resolution of the immune response TFH cells down regulate CXCR5 expression to an intermediate level, but can quickly regain this expression upon secondary challenge.77 Studies have shown that antigen-specific memory CD4+ T cells are better providers of help to B cells than Ag-specific naïve CD4+ T cell controls, and while memory is not strictly lineage-restricted, cell-intrinsic mechanisms favor TFH lineage commitment within memory cell population.78,79

A number of studies have shown the effect of conventional immunosuppression on TFH cells as well as detailing the benefits of TFH targeted therapies. For example, Tacrolimus has been shown to partially inhibit the generation of TFH cells.80 Another study suggested that memory TFH cells may be affected by tacrolimus treatment however more work is needed to confirm these findings.81 The effects of targeting the coinhibitory or costimulatory pathways essential for TFH function in animal models of transplantation have been described in another review.82,83 None of these studies, however, address the direct effects on memory TFH cells, and more work is required to specifically control these cells in transplant settings.

Memory T Peripheral Helper Cells

T peripheral helper (TPH) cells fulfill the role of providing help to B cells outside of the secondary lymphoid organs.30 Phenotypically these cells share many common markers and effector molecules with their follicular TFH counterparts including PD-1, ICOS, TIGIT, CXCL13, and IL-21, but express low levels of TFH defining markers CXCR5 and Bcl6.73 Instead TPH cells express chemokine receptors CCR2 and CCR5 enabling their migration into sites of inflammation.30 These cells are significantly expanded at the sites of peripheral inflammation such as the synovium of rheumatoid arthritis patients84 and are found in the circulation of patients with systemic lupus erythematosus.85 From a functional perspective TPH cells can promote B cell differentiation into plasmablasts in an IL-21 dependent manner.84 Vaccine studies showed that poor responders to influenza vaccination have dysfunctional TPH cells with impaired IL-21 secretion and thus are unable to support IgG production by B cells.86 In transplantation, these cells may pose a significant risk by providing help to B cells in ectopic lymphoid structures (ELS) within the graft. Both kidney and heart allografts can develop ELS that contain donor-specific antibody (DSA) generating plasma cells.87,88 Furthermore, homogenates from kidney allografts undergoing rapid rejection revealed elevated expression of IL-21 mRNA that correlated with the increased expression of activation-induced cytidine deaminase, a marker of B cell activation.89 Taken together these data suggest a link between TPH and allograft rejection via DSA production within ELS. In theory, the same principles that govern therapeutic targeting of TFH should hold true for TPH to prevent or alleviate antibody-mediated rejection.

T Memory Stem Cells

Stem cell like memory T cells or T memory stem cells (TSCM) are a rare newly identified population of memory T cells. Mouse TSCM were initially described as a population with a naïve-like phenotype, but with high expression levels of stem cell antigen 1, IL-2 receptor beta chain, and chemokine receptor CXCR3, the last 2 being memory cell markers.31,32 The novel subset was termed TSCM because of their ability to maintain graft-versus-host disease (GVHD) following serial transplantation into allogenic recipients and due to their ability to reconstitute the full diversity of memory and TEFF cells.31 Human and NHP TSCM are phenotypically identified as coexpressing classical naïve surface markers, CD45RA+ and CD62L+, and memory associated markers including CXCR3, IL-2 receptor beta chain, CD58, CD11a, and CD95 (Table 1).32,33

TSCM have been implicated in maintenance of the immune response to chronic infections, where TEFF cells eventually succumb to exhaustion and thus need to be replaced.90 Studies of chronic viral and parasitic infections have recently demonstrated that there is a negative correlation between disease severity and the frequency of circulating TSCM cells, suggesting their presence is required to replenish exhausted cells.91,92,93 TSCM have also been implicated in disease exacerbation. Elevated frequencies and activation of CD8+ TSCM cells have been found in patients with aplastic anemia, a condition where cytotoxic T cells target hematopoietic progenitor cells.94 In a transplantation study, patients with elevated numbers of TSCM following an immunosuppressive regimen that included antithymocyte globulin induction were at higher risk of treatment failure and subsequent disease relapse.94 This raises interesting questions about the role of TSCM during reconstitution of the immune repertoire following lymphoablation in transplant recipients. In particular, it would be interesting to see how targeted depletion of TSCM in conjunction with a clinically relevant immunosuppressive regimen affects graft outcomes as well as lymphocyte reconstitution kinetics and the reconstituted lymphocyte repertoire.

TARGETING ALLOREACTIVE MEMORY T CELLS: UPDATES ON EXISTING STRATEGIES AND PROMISING ALTERNATIVES

Manipulating Metabolic Pathways

Targeting metabolic pathways has recently emerged as a powerful approach to modulating T cell homeostasis, activation, and functions. Naïve T cells are metabolically quiescent, generating energy via breakdown of glucose, fatty acids, and amino acids to drive oxidative phosphorylation (OXPHOS).95,96,97,98 Transitioning from a resting naïve into a highly proliferative activated state requires extensive metabolic reprogramming. This is driven by a rapid induction of aerobic glycolysis while maintaining mitochondrial OXPHOS and reactive oxygen species output.99,100 While aerobic glycolysis is not the most effective means to generate ATP (2 ATP molecules generated per molecule of glucose compared with 36 molecules of ATP per glucose for OXPHOS), it does confer other metabolic advantages such as the opportunity to synthesize lipids, proteins and carbohydrates, and nucleic acids.101 Additionally, T cells can demonstrate metabolic plasticity switching between aerobic glycolysis and OXPHOS depending upon the nutrient levels of their environment.102,103

Upon activation, extensive metabolic reprogramming is mediated by several signaling pathways and transcription factors. Mammalian target of rapamycin (mTOR) is one of the major regulators in this process. mTOR signaling integrates signals related to nutrient level sensing, stress responses, TCR engagement, and in turn can induce pathways linked to metabolism, cell growth, and proliferation.104,105 mTORc1 activation induces hypoxia-inducible factor 1α (HIF-1α) and Myc, transcription factors that lead to increased glucose uptake, and diversion of glucose from OXPHOS to aerobic glycolysis, and glutaminolysis, respectively.106,107 Another key regulator of T cell metabolism is AMP-activated protein kinase that becomes activated when the ratio of AMP to ATP increases in a metabolic stress sensing function. Transient activation of AMP-activated protein kinase upon TCR stimulation opposes mTOR function and facilitates memory T cell development by promoting catabolic pathways and energy conservation.108,109 Memory T cells do not heavily utilize aerobic glycolysis, and instead prominently rely on OXPHOS, tin part due to the mitochondrial catabolism of fatty acids.110 This process is dependent on free fatty acids generation from triacylglycerols. Triacylglycerol synthesis in turn requires the function of a glycerol channel Aquaporin 9 which is up-regulated in activated T cells in response to IL-7R signaling and supports the survival of memory CD8 T cells.110,111 Recent studies have shown that inhibition of another member of aquaporin family, Aquaporin 4, reduces activation, proliferation, and cytokine production in both naïve and previously sensitized T cells and significantly prolongs mouse heart allograft survival.112,113 Whether the effects of Aquaporin 4 inhibition are mediated through metabolic regulation remains to be elucidated. Nevertheless, targeting aquaporin channels may prove to be a useful future strategy for modulating T cell metabolism.

Memory T cells display a distinct mitochondrial morphology, with more fused networks of mitochondria compared with T effector cells with more isolate and punctate mitochondria.114 However, there are subset variances with TCM and TRM being more reliant on mitochondrial OXPHOS than TEM.115 These metabolic distinctions provide basis for therapeutic manipulations of memory T cell subsets in transplantation, autoimmunity, and cancer. Depending on the type of the disease and on the desired immune response, altering the balance between glycolysis and OXPHOS should facilitate or inhibit memory T cell generation and functions. Studies in cancer have shown that inhibition of glycolysis with 2-deoxyglucose enhances memory T cell formation and provides enhanced anti-tumor activity. However, the study used a genetic approach to enforce glycolytic metabolism and this, in turn, limited CD8+ T cell memory development.116 Similarly, treatment with a different glycolytic inhibitor, dicholoroacetate, was shown to augment CD8 T cell activity and block tumor progression in a mouse model of melanoma.117

Conversely, inhibitors of fatty acid oxidation and mitochondrial OXPHOS should be utilized to control memory T cell activity. In NZB/W and MRL/lpr mouse lupus models, T cells exhibit increased mitochondrial mass and polarization and rely heavily on OXPHOS. The pharmacological inhibition of geranylgeranyltransferase, a component of fatty acid metabolism pathway, not only altered T cell metabolic phenotype but also decreased autoantibody production and lupus nephritis manifestations in these mouse strains.118,119 However, caution should be applied when interpreting such data as the resulting disease is often the sum of effector functions in different T cell subsets. One such example is a mouse study of experimental autoimmune encephalitis model in which glycolysis inhibitor dicholoroacetate promoted Treg functions and diminished pathogenic effector Th17 cells.120 There is accumulating evidence that TRM cells have unique metabolic requirements compared with other memory T cell subsets.121 For example, skin-resident CD8+ TRM cells demonstrate dependency on exogenous free fatty acid acquisition and metabolism that may be exploited therapeutically. Thus in vivo treatment with a pharmacologic fatty acid oxidation inhibitor trimetazidine decreased the survival and maintenance of TRM in skin.122 The efficacy of this approach in targeting CD4+ TRM cells or TRM cells at different anatomic locations warrants further investigation.

Several preclinical studies evaluated the efficacy of metabolic inhibitors in bone marrow and solid organ transplantation. In a model of murine GVHD, a 2-week treatment with a fatty acid metabolism inhibitor etomoxir decreased GVHD scores up to a month after treatment cessation. Etomoxir reduced proliferation and induced apoptosis in the pathogenic CD8+ T cells that were highly proliferative before the treatment whereas nonproliferating cells were spared. In a different study, small molecule inhibitors of the F1F0 ATPase in the electron transport chain have also shown promise in GVHD treatment. The treatment specifically induced apoptosis in the pathogenic cell populations and markedly decreased proinflammatory cytokine production improving GVHD scores and survival rates.123,124 The study by Lee et al125 demonstrated the potency of this approach in 2 mouse models of solid organ transplantation across MHC mismatch barrier. In this work, metabolic reprogramming with inhibitors of glycolysis, glutamine-derived pathways and mitochondrial OXPHOS, abrogated activation induced T cell proliferation, and cytokine production leading to a significant prolongation of skin allograft survival and long-term heart allograft acceptance. Although not done in sensitized recipients, these data clearly demonstrate the power of targeting metabolic pathways in transplantation. Future studies evaluating combinations of agents targeting T cell metabolism with clinically relevant immunosuppression regimens are required to fast-track these therapies from bench to bedside.

Lymphoablation

Antibody-mediated lymphocyte depletion is used as induction therapy in high-risk recipients to overcome the presence of preexisting donor-reactive immunity and has been extensively reviewed previously.126,127,128,129 Multiple preclinical and clinical studies established that a proportion of memory/TEFF cells survives the most common forms of lymphoablative induction, namely anti-CD52 mAb (CAMPATH-1) and ATG. Furthermore, the expansion of depletion-resistant memory T cells has been associated with acute rejection episodes in renal transplant recipients.130 Rodent studies using the same or analogous lymphoablative reagents showed that not only do memory T cells resist depletion but in fact they thrive in the lymphopenic environment, dominate the reconstituted T cell repertoire, and are the principal mediators of allograft rejection under these conditions.130 Notably, memory T cells in nonlymphoid locations such as liver and lung appear to be more resistant to lymphoablation suggesting that the potential pathogenic role of TRM cells in lymphopenic recipients may be amplified.131 Studies by our group demonstrated that the recovery of pathogenic CD8+ T cells was critically dependent on the depletion-resistant memory CD4 helper T cells, B lymphocytes, and CD40/CD154 signaling.131 Consistent with findings in mATG treated mice, a combined therapy of anti-CD154, ATG, and mycophenolate mofetil inhibited donor reactive cellular responses in a robust xenotransplantation pig-to-baboon model.132 Lymphoablation poses challenges of its own and was well demonstrated in a 2014 NHP kidney transplant study, which used a combined therapeutic approach of lymphoablation and belatacept treatments.133 Animals that received combination therapy maintained graft function based on serum creatinine and blood urea nitrogen levels and demonstrated no signs of clinical rejection or detection of alloantibody, but 7 of the 8 animals did succumb to posttransplant lymphoproliferative disorders and infections.

One therapeutic agent that preferentially targets memory/TEFF cells is Alefacept, a fusion protein combining the constant region of human IgG1 with the extracellular domain of LFA-3. LFA-3 is one of the ligands for CD2, a molecule that is upregulated on CD45RO+ effector/memory T cells allowing for more efficient depletion of this population compared with other therapies but still depleting all other subsets.134,135,136 Notably, Alefacept lymphoablation synergized with CTLA4-Ig in improving allograft survival in NHPs presumably due to efficient depletion of CD8+CD2hiCD28 effector memory cells that are typically resistant to costimulatory blockade.137 Unfortunately, despite showing promise in the treatment of plaque psoriasis and in both solid organ and bone marrow transplantation, Alefacept was withdrawn from the market for commercial reasons.134,135,137,138 Nevertheless, targeting CD2 by alternative reagents remains an attractive possibility for lymphoablative induction. The efficacy of anti-CD2 rat mAb BTI-322 in treatment of acute rejection and as induction therapy was demonstrated in renal transplant patients many years ago.139 Recently, the interest in this approach reemerged due to generation of humanized BTI-322, Siplizumab.140,141,142 Siplizumab demonstrated promising safety profile in renal allograft recipients and was successfully used as part of tolerance induction trial in which the majority of HLA-mismatched kidney allograft recipients could successfully be weaned off chronic maintenance immunosuppression for at least 5 years.141,142 The mechanistic studies on Siplizumab were impeded due to its specificity for a binding site present only on the human and chimpanzee CD2 antigen. Most recently, the development of anti-CD2 mAbs with broad primate reactivity provided an opportunity of investigating this approach in more accessible NHP models and is likely to facilitate clinical translation of analogous reagents.143

Lymphoablation is a necessary part of many tolerance induction protocols in rodents and large animals. Mixed chimerism is a state where the hematopoietic cells in the recipient are made up of both donor and recipient cells as a result of bone marrow transplantation following irradiation.144 As a result, graft reactive T cells are negatively selected in the thymus via central tolerance mechanisms. Most importantly, central tolerance can be induced by performing bone marrow transplantation several weeks after solid organ transplantation. The depletion of CD8+ memory T cells, that are normally resistant to radiation, is essential for delayed tolerance induction and prolonged graft survival in NHP models of kidney and lung transplantation.145,146,147 In contrast, studies in mouse models of lung transplantation reported that costimulatory blockade induced graft tolerance is dependent upon the rapid graft infiltration by CD8+ TCM cells.148 These data suggest distinct roles memory T cells play in central versus peripheral tolerance and highlight the potential complexities of translating experimental findings to the clinic.

T Cell Costimulation/Coinhibition

Inhibition of CD28/CD80/CD86 costimulatory pathway at the time of antigen exposure is one of the most potent strategies to prevent T cell activation and induce tolerance.126,18,149 CTLA4-Ig, a fusion protein that binds to CD80/CD86 with high affinity and thus blocks CD28 engagement, is currently on the market in its second iteration, Belatacept. While Belatacept improves allograft survival rates and minimizes toxic side effects of calcineurin inhibitors,150 its use is associated with the increased risk of acute cellular rejection,151,152,153 and the mechanisms of Belatacept-resistant rejection are the subject of active investigations. Over the past 2 decades, studies in animal transplant models revealed that memory T cells are more resistant to CTLA4-Ig treatment. Consistent with these findings, Espinosa et al149,154 identified CD4+CD57+ T cells as possible mediators of Belatacept resistant rejection in renal transplant recipients. The T cells associated with rejection episodes are characterized by elevated expression of adhesion molecules LFA-1, VLA-4, and CD2, decreased surface CD28 expression, and the capacity to produce high levels of effector cytokines. These findings suggested the potential benefits of simultaneously targeting CD28 costimulation and cellular adhesion molecules. Indeed, treatment with monoclonal antibodies blocking LFA-1 and/or VLA-4 prolonged allograft survival in several experimental models, warranting further investigation and potential clinical translation. Thus either anti-LFA-1 or anti-VLA-4 mAb treatment efficiently inhibited costimulatory-blockade resistant rejection of mouse skin allografts mediated by CD8+ memory T cells.155,156,157 Furthermore, study by Setoguchi et al158 demonstrated that a short-course peritransplant treatment with anti-LFA-1 antibodies inhibited early infiltration of endogenous alloreactive CD8+ memory T cells into murine cardiac allografts resulting in significantly prolonged survival.

The clinical application of strategies targeting another key costimulatory pathway, CD40/CD154, was delayed by thromboembolic effects of early anti-CD154 antibodies.159 New generation of blocking anti-CD154 and anti-CD40 antibodies have avoided this complication, and promoted acceptance of various allograft types in mice and NHPs.133,160,161,162 While interference with CD40/CD154 pathway showed great graft-prolonging benefits in robust animal transplantation models including pig-to baboon cardiac transplantation,163 the mechanistic effects of such therapies on reactivation and functions of preexisting donor-reactive memory T cells remain to be determined.

In addition to CD28/B7 and CD40/CD154 costimulation, other costimulatory interactions including ICOS/B7RP-1, CD134/CD134L, CD70/CD27, or CD137/CD137L have been implicated in effector/memory T cell functions. The approaches targeting these pathways showed promise in donor-sensitized recipients, or after delayed administration and have been reviewed elsewhere.18,164 Here we would like to discuss a relatively new addition to the list of T cell coinhibitory molecules, lymphocyte-activating gene 3 (LAG-3/CD223). It is expressed following T cell activation, possibly competes with CD4 for MHC class II binding, and through as yet to be elucidated signaling pathway diminishes T cell responses.165,166,167,168 LAG-3 is also expressed on T regulatory cells and was shown to be key to Treg suppressor function in autoimmunity.169,170 Initial studies in transplant models indicate that LAG-3 deficiency in mice results in augmented T ell memory and accelerates cardiac allograft rejection.171 However, further work is needed to expand on these interesting results and explore the possibility of targeting LAG-3 to ameliorate alloimmune responses. Several reagents targeting LAG-3 activity have been developed and are currently tested in preclinical studies and in clinical trials. One example is a soluble LAG-3 analog that competes with LAG-3 for MHC class II binding and augments immune responses against tumors and viral vaccines.172,173,174 Conversely, a cytolytic chimeric antibody against LAG-3 was shown to deplete LAG-3+ activated T cells and inhibit delayed hypersensitivity response in an NHP model.175 The efficacy of such an approach for selective depletion of effector/memory alloreactive T cells in transplant recipients remains to be tested.

CONCLUSION

Despite rapidly expanding knowledge on memory T cells as efficient mediators of graft rejection, our ability to therapeutically target them in the clinic remains limited. The main challenge is in the very nature of immune memory executed by the variety of cells with broad spectrum of effector functions. Another conceptual problem is that targeting memory T cells based on phenotypic markers lacks specificity and is likely to compromise both pathogenic and protective T cells. Acknowledging anatomical, metabolic, and functional diversity of alloreactive memory T cells should identify new points for pharmacological intervention. The novel approaches targeting generation and recall of memory T cells are currently being developed and tested for applications in cancer, vaccines, and autoimmune diseases and are waiting to be explored in transplant settings. In combination with modern technologies for investigating basic T cell biology, this opens exciting possibilities of scientific discovery and hopefully, therapeutic advances.

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