Seminal studies in mouse models and emerging data in NHP and patient populations have consistently implicated memory T cells as being a formidable barrier to long-term, rejection-free allograft survival, particularly in the setting of costimulation blockade. As such, work in our laboratory over the past several years has focused on identifying new pathways that control memory T cell responses during transplantation. Fc?RIIB, the only inhibitory Fc receptor, inhibits intracellular signaling via the ITIM motif located in its cytoplasmic region. Fc?RIIB is known to be expressed by many immune cell types, including B cells, DCs, macrophages and granulocytes; however, the general consensus for the past few decades has been that T cells do not express this molecule. Work done in the last cycle of the grant published by our lab indicated that Fc?RIIB-/- mice exhibit increased costimulation blockade-resistant rejection relative to WT controls. This increased rejection was not the result of increased antibody secretion, as no differences in anti-donor antibodies were detected in these animals. Instead, we discovered that Fc?RIIB is expressed on a subset of memory CD8+ T cells generated via both transplantation and virally-elicited heterologous immunity, and that blockade of this novel coinhibitory pathway results in enhanced donor-reactive memory CD8+ T cell responses. Our data thus suggest a previously unidentified functional role for Fc?RIIB coinhibitory signaling in regulating CD8+ memory T cells during transplantation. However, the mechanisms underlying this observation, including the identity of the Fc?RIIB ligand in this system (i.e. endogenous antibody vs. Fc-containing biologic), remain unknown. Compellingly, our new preliminary data reveal that the degree of expression of Fc?RIIB on donor- reactive CD8+ memory T cell populations directly correlated with susceptibility of those cells to costimulation blockade, providing further evidence for a T cell-intrinsic role for Fc?RIIB coinhibitory signaling in transplantation. Overall, these data suggest a novel mechanism by which the production of alloantibody may function as a negative feedback loop to prevent alloreactive CD8+ T cell activation, and raise the possibility of an innovative new approach to controlling donor-reactive CD8+ memory T cells during transplantation. Thus, in this proposal we aim to further interrogate the mechanisms by which Fc?RIIB inhibitory signaling regulates donor-reactive memory CD8+ T cell responses in transplantation by determining the T cell intrinsic role of Fc?RIIB signaling, identifying the Fc?RIIB ligand in this system (endogenous antibody/immune complexes vs. Fc-containing biologics), and interrogating the epigenetic and transcription-factor mediated control of Fc?RIIB expression on donor-reactive CD8+ memory T cells during transplantation.
Transplantation is a curative treatment for end-stage organ failure, but rates of significant side-effects remain unacceptably high. New drugs targeting T cell costimulatory pathways (including belatacept) have shown great promise as a less toxic means of preventing T cell responses, however clinical trials have revealed increased rates of acute rejection in belatacept-treated patients, and studies in mouse and non-human primate models have consistently implicated memory T cells as being responsible for mediating belatacept-resistant rejection. In our preliminary studies we have identified a novel protein that can inhibit memory T cell function; thus, in this application we will explore the mechanisms and therapeutic potential of this novel pathway to control memory T cell function and inhibit graft rejection following transplantation.
|Laurie, Sonia J; Liu, Danya; Wagener, Maylene E et al. (2018) 2B4 Mediates Inhibition of CD8+ T Cell Responses via Attenuation of Glycolysis and Cell Division. J Immunol 201:1536-1548|
|Liu, Danya; Badell, I Raul; Ford, Mandy L (2018) Selective CD28 blockade attenuates CTLA-4-dependent CD8+ memory T cell effector function and prolongs graft survival. JCI Insight 3:|
|Morris, Anna B; Adams, Layne E; Ford, Mandy L (2018) Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses. Front Immunol 9:1810|
|Badell, I R; La Muraglia 2nd, G M; Liu, D et al. (2018) Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig. Am J Transplant 18:89-101|
|Bozeman, Alana M; Laurie, Sonia J; Haridas, Divya et al. (2018) Transplantation preferentially induces a KLRG-1lo CD127hi differentiation program in antigen-specific CD8+ T cells. Transpl Immunol 50:34-42|
|Kim, Steven C; Wang, Jun; Dong, Ying et al. (2017) Alloimmunity But Not Viral Immunity Promotes Allograft Loss in a Mouse Model of Polyomavirus-Associated Allograft Injury. Transplant Direct 3:e161|
|Cortes-Cerisuelo, M; Laurie, S J; Mathews, D V et al. (2017) Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients. Am J Transplant 17:2350-2362|
|Winterberg, Pamela D; Ford, Mandy L (2017) The effect of chronic kidney disease on T cell alloimmunity. Curr Opin Organ Transplant 22:22-28|
|Kim, S C; Wakwe, W; Higginbotham, L B et al. (2017) Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. Am J Transplant 17:1182-1192|
|Kitchens, William H; Dong, Ying; Mathews, David V et al. (2017) Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection. JCI Insight 2:e90317|
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