TY - JOUR
T1 - Low-affinity memory CD8+ T cells mediate robust heterologous immunity
AU - Krummey, Scott M.
AU - Martinez, Ryan J.
AU - Andargachew, Rakieb
AU - Liu, Danya
AU - Wagener, Maylene
AU - Kohlmeier, Jacob E.
AU - Evavold, Brian D.
AU - Larsen, Christian P.
AU - Ford, Mandy L.
N1 - Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1500639
DO - 10.4049/jimmunol.1500639
M3 - Article
C2 - 26864034
AN - SCOPUS:84962486551
SN - 0022-1767
VL - 196
SP - 2838
EP - 2846
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -