Low-affinity memory CD8+ T cells mediate robust heterologous immunity

Scott M. Krummey, Ryan J. Martinez, Rakieb Andargachew, Danya Liu, Maylene Wagener, Jacob E. Kohlmeier, Brian D. Evavold, Christian P. Larsen, Mandy L. Ford

Research output: Contribution to journalArticlepeer-review

Abstract

Heterologous immunity is recognized as a significant barrier to transplant tolerance. Whereas it has been established that pathogenelicited memory T cells can have high or low affinity for cross-reactive allogeneic peptide-MHC, the role of TCR affinity during heterologous immunity has not been explored.We established a model with which to investigate the impact of TCR-priming affinity on memory T cell populations following a graft rechallenge. In contrast to high-affinity priming, low-affinity priming elicited fully differentiated memory T cells with a CD45RBhi status. High CD45RB status enabled robust secondary responses in vivo, as demonstrated by faster graft rejection kinetics and greater proliferative responses. CD45RB blockade prolonged graft survival in low affinity-primed mice, but not in high affinity-primed mice. Mechanistically, low affinity-primed memory CD8+ T cells produced more IL-2 and significantly upregulated IL-2Ra expression during rechallenge. We found that CD45RBhi status was also a stable marker of priming affinity within polyclonal CD8+ T cell populations. Following high-affinity rechallenge, low affinity-primed CD45RBhi cells became CD45RBlo, demonstrating that CD45RB status acts as an affinity-based differentiation switch on CD8+ T cells. Thus, these data establish a novel mechanism by which CD45 isoforms tune low affinity-primed memory CD8+ T cells to become potent secondary effectors following heterologous rechallenge. These findings have direct implications for allogeneic heterologous immunity by demonstrating that despite a lower precursor frequency, low-affinity priming is sufficient to generate memory cells that mediate potent secondary responses against a cross-reactive graft challenge.

Original languageEnglish (US)
Pages (from-to)2838-2846
Number of pages9
JournalJournal of Immunology
Volume196
Issue number6
DOIs
StatePublished - Mar 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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