In View: Research Highlights
CD1d-Dependent Immune Suppression Mediated by Regulatory B Cells Through Modulations of iNKT Cells
Oleinika K, Rosser EC, Matei DE, et al. Nat Commun. 2018;9(1):684.
Regulatory B cells (Bregs) are a subpopulation of B cells with immunosuppressive activity mediated chiefly through the secretion of IL-10. There is increasing clinical evidence for Breg activity in maintaining allograft survival. A prime example is the increase in acute rejection rates after B-cell depletion with rituximab.1 IL-10–producing B cells have been detected in tolerant patients, suggesting a role for these cells in maintaining graft survival.2 Despite several studies confirming the existence of Bregs in different disease models, there is no clear consensus regarding their precise phenotype. Bregs are therefore largely defined by their expression of IL-10, with several subsets described including transitional and marginal zone B cells.3 Apart from IL-10 secretion, Bregs have also been found to exert their suppressive activity through the release of IL-35 and TFG-β, in addition to a characteristic PD-L1 expression. There are apparent differences between human and mouse Breg phenotypes, which further complicate their identification and the ability to make comparisons across studies.2 However, a common marker in mouse and human Breg cells is their expression of surface CD1d. CD1d is a nonclassical Major Histocompatibility Complex (MHC) protein involved in lipid antigen presentation.
In the study by Claudia Mauri and co-workers, CD1d on Bregs was found to promote a downregulation of immune responses through its ability to present antigen to iNKT cells.4 These effects promoted IFNγ secretion and subsequently modulated CD4+ T-cell responses, ameliorating experimental arthritis in a mouse model. The activation of iNKT cells by their glycolipid agonist, α-GalCer, has previously been shown to promote the resolution of autoimmunity. The current study defines the central role of Bregs in modifying inflammatory responses. Specifically, depleting B cells reduced IFNγ secretion from iNKT cells and abrogated the ability of α-GalCer to suppress arthritis development. It will be interesting to define if these effects are reproducible in relevant clinical scenarios, as human Bregs also express CD1d. A more in-depth understanding of Breg cell function will be helpful in evaluating their emerging role in the maintenance of clinical graft survival.
- Clatworthy MR, Watson CJ, Plotnek G, et al. B-cell-depleting induction therapy and acute cellular rejection. N Engl J Med. 2009;360:2683–2685.
- Wortel CM, Heidt S. Regulatory B cells: phenotype, function and role in transplantation. Transpl Immunol. 2017;41:1–9.
- Lal G, Nakayama Y, Sethi A, et al. Interleukin-10 from marginal zone precursor b-cell subset is required for costimulatory blockade-induced transplantation tolerance. Transplantation. 2015;99:1817–1828.
- Oleinika K, Rosser EC, Matei DE, et al. CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells. Nat Commun. 2018;9:684.
Effector CD4+ T Cells Recognize Intravascular Antigen Presented by Patrolling Monocytes
Westhorpe CLV, Norman MU, Hall P, et al. Nat Commun. 2018;9(1):747
Transplant rejection is traditionally linked to the infiltration of leukocytes.1 Transendothelial migration, directed at least in part by cognate antigens, is thought to be a critical event in this process.2 For CD8+ T-cell infiltration, recognition of constitutively expressed MHC class I on endothelium is required. For CD4+ T cells, mechanisms are less clear, with MHC class II only expressed on inflamed endothelium. However, there is increasing evidence that leukocytes contribute to inflammatory responses without the need to leave the bloodstream; effects that operate through the production of inflammatory mediators while crawling on endothelium. This so-called intravascular immunity is particularly relevant in glomeruli, where leukocytes have been shown to adhere to and crawl within capillaries.3,4
In their recent publication in Nature Communications, Westhorpe and coworkers investigated mechanisms by which memory CD4+ T cells recognize antigens in a model of glomerulonephritis.5 Using multiphoton intravital microscopy, CD4+ T cells were found to adhere to uninflamed glomerular capillaries. As expected, the presence of cognate antigen (using a transgenic T-cell receptor model) enhanced recruitment and adhesion of CD4+ T cells. Interestingly, in a noninflamed state, MHC class II expression within glomeruli was mainly restricted to monocytes. Mice depleted of monocytes had a reduction in inflammatory responses produced by crawling CD4+ T cells, highlighting the important role of antigen presentation by monocytes in mediating intravascular immunity.
Although the model used in this study was that of a nontransplant glomerulonephritis, there are clear implications for transplantation. In the inflamed state, antigen recognition is likely to take place through endothelial expression of MHC class II. However, in the steady state, there may be a role for monocyte-mediated intravascular immunity in the promotion of T-cell recruitment and activation through indirect allorecognition.
- Wood KJ, Goto R. Mechanisms of rejection: current perspectives. Transplantation. 2012;93:1–10.
- Walch JM, Zeng Q, Li Q, et al. Cognate antigen directs CD8+ T cell migration to vascularized transplants. J Clin Invest. 2013;123:2663–2671.
- Finsterbusch M, Hall P, Li A, et al. Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus. Proc Natl Acad Sci U S A. 2016;113:E5172–E5181.
- Devi S, Li A, Westhorpe CL, et al. Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus. Nat Med. 2013;19:107–112.
- Westhorpe CLV, Norman MU, Hall P, et al. Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes. Nat Commun. 2018;9:747.