CD154 blockade alters innate immune cell recruitment and programs alloreactive CD8+ T cells into KLRG-1(high) short-lived effector T cells.
CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-K(d)) to B6 (H2-K(b)) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8(+) T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44(high) CD62L(low) CD8(+) T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8(+) T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8(+) T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1(low) long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8(+) T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1(low) memory precursor cells.
Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, United States of America.
Ivana R
IR
Ferrer
Maylene E
ME
Wagener
Mingqing
M
Song
Mandy L
ML
Ford
D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D054405:Chemokine CCL3 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D006085:Graft Survival / Q000276:immunology; D007113:Immunity, Innate; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000378:metabolism*; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014184:Transplantation, Homologous
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D016207:Cytokines; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D023201:CD40 Ligand