CD11b: A Novel Alternate Receptor for CD154 during Alloimmunity

Emory University, Atlanta GA

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Abstract

Summary Blockade of CD154 during transplantation is a highly effective means of inhibiting alloreactive T cell responses and inducing long-term survival of allografts, but clinical translation of this pathway has been circuitous and fraught with challenges. However, CD40 blockers have shown consistent and significant inferiority as compared to CD154 blockers in both preclinical studies and clinical trials. Thus, here we seek to understand the mechanistic differences underlying CD154 vs. CD40 blockers in order to optimize the therapeutic potential of this pathway for use in transplantation. During the last funding cycle, we reported that CD11b is a novel alternate receptor for CD154 during alloimmunity, and that it plays a CD40-independent role in driving local inflammation within allografts. However, the mechanisms underlying this are unknown. In this application, we present compelling new data to suggest that CD11b functions as a novel cell autonomous costimulator of clinically-relevant alloreactive CD8+ T cells. This hypothesis is based on new preliminary data showing that CD11b is significantly upregulated on donor-reactive and graft-infiltrating CD8+ T cells in a murine model. More compellingly, analysis of single cell RNA-sequencing data from graft-infiltrating cells isolated from renal transplant recipients experiencing belatacept-resistant rejection revealed a cluster of CD11b+ CD8+ T cells. These new preliminary data from human renal transplant recipients therefore identify a CD11b+ CD8+ T cell subset that may underlie belatacept-resistant rejection. Given these clinical results, we asked if CD11b plays a functional role on CD8+ T cells. In a murine transplant model, we found that conditional deletion of CD11b from CD8+ T cells results in significant reduction in the accumulation of antigen-specific CD8+ T cell populations. Therefore, in this application we will interrogate the mechanisms by which CD11b functions as a clinically relevant cell-autonomous costimulator of CD8+ T cells. Given our recently published results showing that CD154 is a key ligand for CD11b in driving alloimmunity, these results suggest the novel hypothesis that CD11b+ CD8+ T cells receive direct costimulation via CD154. A corollary of this hypothesis is that CD154 blockade would inhibit these CD11b+, CD28-independent CD8+ T cells, forming the cellular and molecular basis for the impressive synergy observed when blocking these two pathways in promoting transplantation tolerance. Moreover, our preliminary data show that CD154 is upregulated on DC following innate allorecognition, leading us to form the hypothesis that CD154 expressed on DC within the graft provides costimulation for CD11b+ CD8+ T cells. These hypotheses will be tested using rigorous mechanistic experiments in mouse models, in vitro experiments using belatacept-resistant human T cells, and via use of a novel nanotherapeutic approach to synergistically target CD154:CD11b interactions and improve belatacept- resistant rejection.