γδ T cells comprise approximately 1% to 10% of T lymphocytes in human peripheral blood; however, in skin, intestine, lungs, spleen, and liver, they can be the major proportion of residing T cells.1 γδ T cells bridge innate and adaptive immunities and perform a diverse array of functions, including direct lysis of infected or transformed cells and the production of inflammatory and chemotactic chemokines. Relevant to alloimmunity, they also play a role in dendritic cell maturation, CD4+ and CD8+ T-cell priming and promotion of antibody production.1 Given their diverse location and function, it is somewhat surprising they have received relatively little attention concerning their role in transplantation outcome. In this issue of Transplantation, McCallion and colleagues2 review the current literature regarding the impact of γδ T cells after transplantation.
Compared with conventional αβ T cells, the T-cell receptor (TCR) repertoire of γδ V and J gene segments is more restricted, with the gamma and delta TCR loci containing 6 and 8 functional variable (V) segment genes, respectively.1 Populations of γδ T cells with distinct TCR usage reside in anatomically different localizations. For example, Vγ5Vδ1 γδ T cells are found in skin epidermis, and Vγ6Vδ1 γδ T cells are localized in the lung, peritoneum, tongue, and reproductive organs.3 The majority of peripheral blood γδ T cells use the Vγ9 and Vδ2 chains and are thought to predominantly recognize phosphoantigens.1 Epithelia, including intestine, lung and liver, contain mostly γδ T cells using Vδ1, Vδ3 or Vδ5 segments and are together referred to as “Vδ2neg γδ T cells” and recognize stress-related antigens, although the nature of such ligands remains uncharacterized.4 In addition to the TCR, γδ T cells express natural killer (NK) cell receptors, such as NKG2D, NKp30, NKp44, and DNAM-1.5 This allows γδ T to recognize cells that have upregulated stress- or damaged-induced ligands, a mechanism that could be important after transplantation. Moreover, many γδ T cells express the low-affinity Fc receptor CD16, leading to the recognition of IgG opsonised pathogens or target cells and promoting their activation without TCR engagement.4 γδ T cells can also undergo adaptive clonal expansion in response to viral infection, a feature that is characteristic of an adaptive TCR-antigen driven interaction. Although some features of γδ T cells may be applicable to all transplant scenarios, such as their role in pathogen immunity, other functions of γδ T cells are tissue-specific. In this case, the particular properties of tissue-resident γδ T cells should also be considered in solid-organ transplantation.
In their article, McCallion et al2 present literature providing evidence that γδ T cells are both beneficial and detrimental after transplantation, in many respects akin to the literature on NK cells in transplantation. Through immunoregulatory mechanisms, γδ T-cell subsets reportedly play a role in transplant tolerance, including renal,6 liver,7 and islet8 allografts, and are also associated with positive engraftment and reconstitution after hematopoetic stem-cell transplantation (HSCT).1 Furthermore, the authors observed that the antiviral properties of γδ T cells may positively influence posttransplantation outcomes. Cytomegalovirus (CMV) drives the expansion of Vδ2neg γδ T cells, parallel to that seen for CMV-specific CD8+ T cells. Given that CMV remains the most common infectious insult after transplantation, there is much interest in developing new therapies and prognostic tests for monitoring posttransplant CMV immunity. Although originally observed in renal transplant recipients, the potential of Vδ2neg γδ T cells to limit CMV replication in HSCT and in recipients of other solid organ transplants is significant,9 yet monitoring such populations posttransplant has been largely overlooked. Furthermore, similar populations could control other opportunistic microbial pathogens after transplantation. Moreover, due to TCR-dependent cross-reactivity on tumor cells, CMV-induced Vδ2- γδ T cells are associated with lower cancer occurrence post-renal transplant.9 On the other hand, and highlighting the truly dichotomous nature of γδ T cells, CMV-induced γδ T cells express CD16 and could potentially be involved in antibody-mediated injury of allografts.9 γδ T cells may also contribute to allograft rejection via IL-17–dependent mechanisms.10 The role for γδ T cells in graft-versus-host disease after HSCT is mixed with evidence for different populations promoting or repressing graft-versus-host disease.1
It is evident we should be paying attention to γδ T cells after transplantation. Unveiling the ligands for γδ T cells as well as understanding the different function and mechanism of activation of distinct γδ T-cell subsets are all key to understanding their role in transplantation. Ultimately, this would lead to harnessing γδ T cells for promoting tolerance and immunity to infection while avoiding their potential to mediate destruction of allograft tissue.
1. Minculescu L, Sengelov H. The role of gamma delta T cells in haematopoietic stem cell transplantation. Scand J Immunol
2. McCallion O, Hester J, Issa F. Deciphering the conibution of γδ T Cells to outcomes in transplantation. Transplantation
3. Paul S, Shilpi, Lal G. Role of gamma-delta (γδ) T cells in autoimmunity. J Leukoc Biol
4. Khairallah C, Déchanet-Merville J, Capone M. γδ T cell-mediated immunity to cytomegalovirus infection. Front Immunol
5. Silva-Santos B, Strid J. Working in "NK Mode": natural killer group 2 member D and natural cytotoxicity receptors in stress-surveillance by γδ T cells. Front Immunol
6. Zhou J, Appleton SE, Stadnyk A, et al. CD8+ gammadelta T regulatory cells mediate kidney allograft prolongation after oral exposure to alloantigen. Transpl Int
7. Zhao X, Li Y, Ohe H, et al. Intragraft Vδ1 γδ T cells with a unique T-cell receptor are closely associated with pediatric semiallogeneic liver transplant tolerance. Transplantation
8. Hu M, Wu J, Zhang GY, et al. Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice. Cell Transplant
9. Couzi L, Pitard V, Moreau JF, et al. Direct and indirect effects of Cytomegalovirus-Induced γδ T cells after kidney transplantation. Front Immunol
10. Kimura N, Nakae S, Itoh S, et al. Potential role of γδ T cell-derived IL-17 in acute cardiac allograft rejection. Ann Thorac Surg