Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 45, Pages 19461-19466Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1011748107
Keywords
costimulation; T-cell expansion; programmed cell death
Categories
Funding
- British Heart Foundation [PG/05/136/19997, RG/09/002]
- Wellcome Trust [081172/Z/06/Z]
- National Institutes of Health [R01 CA084040]
- Cancer Research UK [C26587/A8839]
- Biotechnology and Biological Sciences Research Council [BB/F020732/1, BB/E009867/1, BBS/E/B/0000C236, BB/C509890/1] Funding Source: researchfish
- British Heart Foundation [RG/09/002/26425] Funding Source: researchfish
- BBSRC [BB/E009867/1, BB/F020732/1, BBS/E/B/0000C236] Funding Source: UKRI
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CD31 is an Ig-like molecule expressed by leukocytes and endothelial cells with an established role in the regulation of leukocyte trafficking. Despite genetic deletion of CD31 being associated with exacerbation of T cell-mediated autoimmunity, the contribution of this molecule to T-cell responses is largely unknown. Here we report that tumor and allograft rejection are significantly enhanced in CD31-deficient mice, which are also resistant to tolerance induction. We propose that these effects are dependent on an as yet unrecognized-role for CD31-mediated homophilic interactions between T cells and antigen-presenting cells (APCs) during priming. We show that loss of CD31 interactions leads to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells. Immunomodulation by CD31 signals correlates with a partial inhibition of proximal T-cell receptor (TCR) signaling, specifically Zap-70 phosphorylation. However, CD31-deficient mice do not develop autoimmunity due to increased T-cell death following activation, and we show that CD31 triggering induces Erk-mediated prosurvival activity in T cells either in conjunction with TCR signaling or autonomously. We conclude that CD31 functions as a nonredundant comodulator of T-cell responses, which specializes in sizing the ensuing immune response by setting the threshold for T-cell activation and tolerance, while preventing memory T-cell death.
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