title: Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity.
abstract: The affinity of a TCR binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low-affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic Ag and mediate graft rejection. We found that low-affinity-primed memory CD8(+) T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared with high-affinity-primed memory T cells. Low-affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2(hi) proliferating cells. Low-affinity-primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low- but not high-affinity-primed animals. These data establish a functional connection between TNF signaling and TCR-priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Krummey
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Sara A
authors.identifier: 0000-0002-5275-1821
authors.initials: SA
authors.lastname: Guasch
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Danya
authors.identifier: 0000-0001-6103-6486
authors.initials: D
authors.lastname: Liu
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Maylene
authors.initials: M
authors.lastname: Wagener
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA 30322 mandy.ford@emory.edu.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D006084:Graft Rejection / Q000276:immunology*; D064789:Immunity, Heterologous; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D016038:Skin Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha