Introduction– While it is well known that CD4+ T cells and B cells collaborate for antibody (Ab) production, our group has recently reported a novel mechanisms of alloAb inhibition mediated by that CD8+ T cells. However, the exact mechanism of CD8-mediated inhibition of alloAb levels remains unclear. We have also reported that alloAb production is enhanced in perforin KO and FasL KO transplant (Tx) recipients. Therefore, we hypothesized that alloprimed CD8+ cytotoxic T cells downregulate alloAb production by killing Ab producing B cells. Methods– We adoptively transferred (AT) wild-type (WT), FasL-deficient, or perforin-deficient CD8+ T cells into CD8 KO hepatocyte recipients (day 0). Serum alloAb levels were measured on day 14 postTx. Additionally, we utilized an in vivo and in vitro cytotoxicity assays to investigate whether alloprimed IgG1+ B cells are preferentially cleared by CD8-dependent mechanisms. Results– We found that while CD8 KO recipients exhibit high alloAb production, the AT of WT CD8+ T cells into CD8 KO recipients significantly reduced serum alloAb. However, AT of CD8+ T cells which lacked FasL or perforin was less effective in reducing alloAb. Utilizing an in vivo cytotoxicity assay, we found that alloprimed IgG1+ (Ab producing) B cells are preferentially killed in CD8 KO recipients AT with WT CD8+ T cells. CD8+ T cells deficient in FasL or perforin had significantly reduced cytotoxicity towards IgG1+ B cells. A in vitro cytotoxicity assay revealed that alloprimed IgG1+ B cells underwent apoptosis when co-cultured with bulk alloprimed CD8+ T cells but not when co-culture with naÏve CD8+ T cells or bulk third party activated CD8+ T cells. Furthermore, MHC I-deficient alloprimed IgG1+ B cells did not undergo apoptosis in CD8/B cell co-cultures suggesting that CD8+ T cells directly kill alloprimed IgG1+ B cells through TCR/MHC I interactions. Conclusion– This data is consistent with the interpretation that alloprimed CD8+ T cells downregulate postTx alloAb production by the use of specific cytotoxic effector molecules for direct elimination of alloprimed IgG1+ B cells. Clinical identification of a specific subset of CD8+ CTLs that recognize primed B cells through allopeptide/self MHC I complexes could translate into clinical strategies to induce alloAb suppression without influencing allograft rejection or immunity to infectious diseases.
To cite this abstract in AMA style:Zimmerer J, Pham T, Tobin K, Sanders V, Bumgarder G. CD8+ Cytotoxic T Cells Inhibit Alloantibody Production by Killing Alloprimed B Cells [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/cd8-cytotoxic-t-cells-inhibit-alloantibody-production-by-killing-alloprimed-b-cells/. Accessed July 24, 2021.
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