Abstract
BackgroundThe 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.ResultsWe 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 naïve 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-γ, 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-β1 completely and IFN-γ partially suppressed the CD57+ GC-Th cell-driven Ig production.ConclusionsCD57+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-β.
Highlights
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
CD57+CD4+ T cells in the germinal centers of human lymphoid tissues are the major T helper cell subset for germinal center B (GC-B) cells in Ig synthesis. Their helper activity is consistent with their capacity to induce activation-induced cytosine deaminase (AID) and class switch recombination, and can be regulated by CD40L, IL-4, IL-10 and TGF-β
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 in naïve vs. germinal center B (GC-B) cells in comparison with other T cell subsets in human tonsils
Summary
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. CD57+ GC-Th cells express the B-cell zone homing chemokine receptor CXCR5 but not the T cell zone homing chemokine receptor CCR7, a pattern consistent with their specific localization in GC [19] Based upon their non-polarized cytokine profile, localization in GC and potential helper activity, it has been proposed that CD57+ GC-Th cells may constitute a novel effector T cell subset distinct from other well known effector T cell subsets such as Th1 and Th2 cells [20]. The microarray study revealed that CD57+ GC-Th cells have the unique capacity to produce CXCL13, a follicle chemokine implicated in recruitment of CXCR5+ cells [22,23] and development of follicles/GCs [24] Because of their specific localization in germinal centers, the activities of CD57+ GC-Th cells on B cell proliferation and antibody production have been studied by several groups of scientists [19,25,26,27]. The results of these previous studies reveled unique features of CD57+ GC-Th cells, but, when combined, they are inconclusive and widely vary from negative to neutral or positive in assessing the helper activities of CD57+ GC-Th cells
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