title: Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity.
abstract: Heterologous immunity is recognized as a significant barrier to transplant tolerance. Whereas it has been established that pathogen-elicited 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 CD45RB(hi) 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-2Rα expression during rechallenge. We found that CD45RB(hi) status was also a stable marker of priming affinity within polyclonal CD8(+) T cell populations. Following high-affinity rechallenge, low affinity-primed CD45RB(hi) cells became CD45RB(lo), 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.
authors: Emory Transplant Center, Atlanta, GA 30322; and.
authors: Scott M
authors: SM
authors: Krummey
authors: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322.
authors: Ryan J
authors: RJ
authors: Martinez
authors: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322.
authors: Rakieb
authors: R
authors: Andargachew
authors: Emory Transplant Center, Atlanta, GA 30322; and.
authors: Danya
authors: D
authors: Liu
authors: Emory Transplant Center, Atlanta, GA 30322; and.
authors: Maylene
authors: M
authors: Wagener
authors: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322.
authors: Jacob E
authors: JE
authors: Kohlmeier
authors: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322.
authors: Brian D
authors: BD
authors: Evavold
authors: Emory Transplant Center, Atlanta, GA 30322; and.
authors: Christian P
authors: CP
authors: Larsen
authors: Emory Transplant Center, Atlanta, GA 30322; and mandy.ford@emory.edu.
authors: Mandy L
authors: ML
authors: Ford
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003429:Cross Reactions; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D016038:Skin Transplantation
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D017493:Leukocyte Common Antigens