Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination

Background: The function of CD57(+) CD4(+) T cells, constituting a major subset of germinal center T (GC-Th) cells in human lymphoid tissues, has been unclear. There have been contradictory reports regarding the B cell helping function of CD57(+) GC-Th cells in production of immunoglobulin (Ig). Furthermore, the cytokine and co-stimulation requirement for their helper activity remains largely unknown. To clarify and gain more insight into their function in helping B cells, we systematically investigated the capacity of human tonsil CD57(+) GC-Th cells in inducing B cell Ig synthesis. Results: We demonstrated that CD57(+) GC-Th cells are highly efficient in helping B cell production of all four subsets of Ig ( IgM, IgG, IgA and IgE) compared to other T-helper cells located in germinal centers or interfollicular areas. CD57(+) GC-Th cells were particularly more efficient than other T cells in helping GC-B cells but not nave B cells. CD57(+) GC-Th cells induced the expression of activation-induced cytosine deaminase ( AID) and class switch recombination in developing B cells. IgG1-3 and IgA1 were the major Ig isotypes induced by CD57(+) GC-Th cells. CD40L, but not IL-4, IL-10 and IFN-gamma, was critical in CD57(+) GC-Th cell-driven B cell production of Ig. However, IL-10, when added exogenously, significantly enhanced the helper activity of CD57(+) GC-Th cells, while TGF-beta 1 completely and IFN-gamma partially suppressed the CD57(+) GC-Th cell-driven Ig production. Conclusions: CD57(+) CD4(+) T cells in the germinal centers of human lymphoid tissues are the major T helper cell subset for GC-B cells in Ig synthesis. Their helper activity is consistent with their capacity to induce AID and class switch recombination, and can be regulated by CD40L, IL-4, IL-10 and TGF-beta.