Germinal Center B Cells are Uniquely Targeted by Antibody-Suppressor CXCR5⁺CD8⁺ T Cells

Background: Alloprimed antibody-suppressor CXCR5⁺CD8⁺ T cells (CD8⁺ T_Ab-supp cells) downregulate alloantibody production, mediate cytotoxicity of IgG⁺ B cells, and prolong allograft survival. The purpose of this investigation was to determine which immune-cell subsets are susceptible to CD8⁺ T_Ab-supp cell-mediated cytotoxicity or noncytotoxic suppression.

Methods: Alloprimed immune-cell subsets were evaluated for susceptibility to CD8⁺ T_Ab-supp cell-mediated in vitro cytotoxicity and/or suppression of intracellular cytokine expression. In vivo CD8-mediated cytotoxicity to wild-type germinal center (GC) B cells or wild-type CD4⁺ T follicular helper cells (T_FH cells) was assessed in RAG1 knockout mice. The impact of in vivo adoptive transfer of CD8⁺ T_Ab-supp cells into hepatocyte or kidney transplant recipients on the quantity of lymphoid immune-cell subsets was assessed.

Results: CD8⁺ T_Ab-supp cells mediated allospecific cytotoxicity to alloprimed GC B cells but not alloprimed extrafollicular plasmablasts, marginal zone B cells, follicular B cells, or plasma cells. CD8⁺ T_Ab-supp cells did not mediate cytotoxicity to alloprimed dendritic cells, macrophages, CD4⁺ T_FH cells, CD4⁺ T follicular regulatory cells, or CD4⁺ regulatory T cell. CD8⁺ T_Ab-supp cells did not suppress CD4⁺ T_FH cell, T follicular regulatory cell, or regulatory T-cell cytokine expression. Adoptive transfer of CD8⁺ T_Ab-supp cells into hepatocyte or kidney transplant recipients reduced alloantibody production and the quantity of GC B cells, T_FH cells, and plasma cells (but not other B-cell, T-cell, or antigen-presenting cell subsets). The reduction of T_FH-cell quantity was dependent on CD8⁺ T_Ab-supp cell-mediated major histocompatibility complex-I-dependent cytotoxic killing of GC B cells.

Conclusions: The primary targets of CD8⁺ T_Ab-supp cells are GC B cells with downstream reduction of T_FH and plasma cells.