Alloantibodies (alloAb) play a critical role in acute and chronic rejection after transplantation (Tx). It is well known that CD4⁺ T cells and B cells collaborate for antibody (Ab) production. Our group has reported, in a well-characterized murine hepatocyte (Hc) Tx model, that alloAb production requires CD4⁺ T cells, type I NKT cells, lymph nodes, and CD40/CD40L interactions. In contrast, we have recently reported a novel Ab-suppressing CD8⁺ T cell subset, or CD8⁺ T_Ab-supp cells, that inhibits alloAb production postTx, in part by killing alloAb producing IgG1⁺ B cells. In addition, we have also reported that CD8⁺ T_Ab-supp cells inhibit the number of splenic IL-4⁺CD4⁺ T cells detected in vivo postTx. In order to further investigate the cellular targets and mechanisms of CD8⁺ T_Ab-supp cell effector function, we utilized OVA antigen [from C57BL/6 mOVA transgenic Hc lysate (H-2^b)] to stimulate anti-OVA antibody. Similar to CD8⁺ T_Ab-supp cell postTx, OT-I Tg CD8⁺ T cells (specific to OVA antigen) negatively regulate the quantity of anti-OVA Ab produced in mOVA treated CD8 KO recipients (285±21 ng/mL with adoptive transfer of OT-I cells vs 519±97 ng/mL without CD8⁺ T cells; p=0.01) and kill IgG1⁺ B cells (22±3% in vivo B cell apoptosis vs 4±0.9% for naïve OT-I Tg CD8⁺ T cells; p<0.001). We hypothesized that CD8⁺ T_Ab-supp cells inhibit Ab titer by downregulating cells in the germinal center (GC) including CD4⁺ T_FH cells (CXCR5⁺ICOS⁺PD-1⁺CD4⁺ T cells) and GC B cells (B220⁺CXCR5⁺CXCR4⁺GL-7⁺ B cells). Following adoptive transfer of OT-I CD8⁺ T cells into CD8 KO mOVA treated recipients, the number of IL-21⁺CD4⁺ T_FH cells (2.3±0.1 x10⁴ cells/million CD4⁺ T cells) was significantly decreased compared to untreated CD8 KO mOVA recipients (4.2±0.2 x10⁴ cells/million CD4⁺ T cells; p=0.01). In addition, the number of GC B cells were significantly reduced by AT of OT-I Tg CD8⁺ T cells into CD8 KO mOVA stimulated recipients (5±0.6 x10³ cells/million B cells) compared to mOVA treated CD8 KO mice (13.1±0.9 x10³ cells/million B cells; p=0.02). This data suggests that CD8⁺ T_Ab-supp cells inhibit Ab production through at least two mechanisms including the inhibition of maturation and/or effector function of IL-21⁺CD4⁺ T_FH cells and killing GC B cells.

CITATION INFORMATION: Zimmerer J, Avila C, Elzein S, Ringwald B, Warren R, Bumgardner G. CD8+ TAb-supp Cells Are Key Inhibitors of Humoral Alloimmunity by Inhibiting CD4+TFH Cells and Killing Germinal Center B Cells. Am J Transplant. 2017;17 (suppl 3).

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