We have reported that a CD8⁺ T cell subset, we termed CD8⁺ T_Ab-supp cells, inhibits the production of alloAb after hepatocyte transplant (HcTx) in part by killing alloprimed IgG1⁺ B cells. The purpose of this study was to determine whether alloantibody produced following transplant of islet and vascularized skin allografts are susceptible to regulation by CD8⁺ T_Ab-supp cells as has been observed for HcTx. CD8-replete or CD8-deficient mice [C57BL/6, CD8 KO, and CD8 KO adoptively transferred (AT) with CD8⁺ T cells; H-2^b] were transplanted with Hc, islet, or skin allografts (FVB/N; H-2^q). Methods: We adoptively transferred (AT) CD8⁺ T cells into CD8 deficient (CD8 KO) Tx recipients and assayed alloab titer, isotypes, MHC specificity and in vivo CD8 T cell cytotoxicity to alloprimed B cells.Results: We found that in all Tx models, alloAb titer was significantly higher in CD8 KO recipients and downregulated in wild-type (C57BL/6) and CD8 KO recipients AT with CD8⁺ T cells (day 0 AT; p<0.005 for all Tx models). While HcTx drives production of only IgG1 (with limited specificity to MHC I) islet and skin transplants produce multiple isotypes (IgG1, IgG2b, IgG2c, and IgG3) without a dominant isotype and with specificity to both MHC I and MHC II. This suggests that CD8⁺ T_Ab-supp cells inhibit the production of all Ab isotypes and both MHC class I and class II alloantibody postTx. In vivo cytotoxicity assays against IgG1⁺ or IgG2b⁺ B cell targets showed that CD8⁺ T_Ab-supp cells (day 7 postTx) kill both IgG1⁺ (34±6%) and IgG2b⁺ alloprimed B cells (43±12%) compared to 3^rd party controls (2±0.5; p<0.04 for both). These data suggest that CD8⁺ T_Ab-supp cells downregulate the production of multiple alloAb isotypes with specificity for both donor MHC class I and II in part through CD8-mediated killing of alloprimed B cells which develop following cellular or vascularized Tx.

CITATION INFORMATION: Zimmerer J, Avila C, Elzein S, Ringwald B, Bumgardner G. CD8+ TAb-supp Cells Suppress the Production of Multiple Alloantibody Isotypes in Response to MHC-Mismatched Cellular and Vascularized Allografts. Am J Transplant. 2017;17 (suppl 3).

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