Expression of Sirpα Tailless Mutant in Mice Impairs Naïve CD4+ T Cell Adhesion to Immobilized ICAM‐1 and TCR Induced Proliferation.

Abstract

Signal Regulatory Protein alpha (SIRPα) interaction with its ligand CD47 plays an important role in immune cell homeostasis. CD47 is expressed by essentially all cell types, and acts as a “don't eat me signal” and a marker of self. We previously demonstrated that CD47 on both endothelium and T cells plays an important role in T cell adhesion and diapedesis in vivo and in vitro, and that CD47−/− CD4+ T cells had impaired antigen mediated proliferation in a model of Experimental Autoimmune Encephalomyelitis (EAE). In contrast to CD47, SIRPα has been reported as selectively expressed in the Central Nervous System (CNS), in most myeloid cells and at very low levels‐to‐absent in lymphoid cells in humans. To gain insight into the function of SIRPα in leukocyte recruitment, Sirpα truncated cytoplasmic, non‐signaling mutant (Sirpatm1Nog) transgenic mice and WT mice were studied in TNFα‐induced dermal air pouch model of inflammation. Unexpectedly, CD4+ T cells in Sirpatm1Nog mice, compared to WT mice, had significantly decreased recruitment into the air pouch (WT, 11.9 ± 2.9 ×103 vs Sirpatm1Nog, 7.8 ± 2.6 ×103, p<0.05), whereas no differences in CD8+ T cell or myeloid cell recruitment were observed. Interestingly, flow cytometric analysis using P84 monoclonal antibody showed that a low but significant fraction of CD4+ T cells in both WT and Sirpatm1Nog mice expressed SIRPα. Expression of Very Late Antigen‐4 (VLA‐4) and Lymphocyte Function Associated Antigen‐1 (LFA‐1) integrins, which are ligands of Vascular Cell Adhesion Molecule‐1 (VCAM‐1) and Intercellular Adhesion Molecule‐1 (ICAM‐1), respectively, were similar in T cells from WT and Sirpatm1Nog mice. Additional studies showed naïve CD4+ isolated from Sirpatm1Nog, compared to WT mice, had significantly blunted proliferation 48 hrs after T cell receptor crosslinking (TCR‐XL), and that CD4 T cells had impaired SDF‐1α induced arrest on immobilized ICAM‐1 under shear flow conditions. In summary, these studies demonstrate that SIRPα plays an unexpected and important role in T cell recruitment in vivo and in vitro and in TCR‐XL induced proliferation in vitro. These data suggest that loss of SIRPα signaling in SIRPα+ T cells leads to impaired LFA‐1 activation.Support or Funding InformationR01 HL125780 and T32HL007627.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.