The novel role of HLA-E restricted CD8 regulatory T cells in kidney allograft rejection

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Antibody-mediated rejection (AMR) in kidney transplantation remains a major cause of kidney graft loss and a critical hurdle to improve long term allograft survival, with no approved therapy. Antibody responses are tightly controlled through T follicular helper (Tfh) cells. Understanding the role of Tfh in kidney transplant and developing clinically translatable strategies to control AMR holds promise to improve long term outcomes. Our group has identified that Qa-1(HLA-E in human) restricted CD8 Tregs are critical regulators of Tfh, the key modulators of B cell differentiation in the germinal center (GC) in kidney transplantation. CD8 Tregs are confined to <5% of CD8 T cells that express a triad of surface receptors– CD44, CD122 and Ly49. Our recently published data (Choi et al. PNAS, Dec 2020) and preliminary data describe a novel role for CD8 Treg in regulating Tfh in allo-immunity. These CD8 Tregs express T cell receptors (TCRs) that recognize Qa-1, a non-classical class-Ib MHC molecule with limited polymorphism. We show that alloreactive activated CD4 T cells, especially Tfh, upregulate their Qa-1 expression, making them a target for CD8 Treg suppression. Disrupting the peptide Qa-1 (pQa-1)-TCR interaction via a point mutation in the Qa-1 gene while sparing the binding of pQa-1 to the inhibitory NKG2A receptor on CD8 Treg leads to the uncontrolled proliferation of Tfh, B Cell maturation, increased donor specific antibodies (DSA), increased allograft complement activation, and accelerated allograft rejection. Our preliminary data show that mobilization and activation of CD8 Treg by specific peptide FL9 agonists dampen Tfh-dependent anti-graft Ab-mediated injury and prolong fully mismatched kidney allograft survival. Since HLA-E and Qa-1 are expressed as only 1 of 2 alleles, this approach is applicable to large groups of patients and avoids the problems of MHC class Ia diversity. The clinical feasibility of FL9 peptide therapy to AMR has high translational potential in AMR and highlights the significance of this approach. Our hypothesis is that during alloimmune T cell activation in kidney transplantation, alloreactive T cells, primarily Tfh, upregulate Qa-1- stress peptide complexes, mostly FL9 on their surface, allowing tight control by Qa1 restricted CD8 Treg. Furthermore, LY49 expressed on CD8 Treg serve as a coinhibitory signal. Identifying peptides critical for the control of alloreactive T cells by antigen specific CD8 Tregs and the positive and negative signals critical for their function will lead to novel targeted therapeutic strategies in allo-immunity and will be investigated here. To test our hypothesis, we developed multiple new tools that are unique to our group. We generated super agonists for the stress peptides to optimize in vivo CD8 Tregs expansion. We also generated a new transgenic mouse where CD8 T cells express TCR that specifically recognize FL9-Qa1 peptide complex. While LY49 may have inhibitory function on CD8 Tregs, we will study its role in allo-immunity through a newly generated knockout mouse and blocking antibodies developed in our laboratory. We will test this hypothesis in murine kidney transpant model that leads to cellular and antibody mediated rejection similar to human rejection.