The Journal of Allergy and Clinical Immunology, October 2015, Vol.136(4), pp.993-1006.e1
Follicular helper T (T ) cells underpin T cell–dependent humoral immunity and the success of most vaccines. T cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of T cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT ) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in , , , , , , , , , , , or . Loss-of-function (LOF) mutations in , , , , , or reduced cT cell frequencies. and LOF and gain-of-function mutations skewed cT cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cT cell function and , as corroborated by hypergammaglobulinemia in patients with , , and LOF mutations. Specific mutations affect the quantity and quality of cT cells, highlighting the need to assess T cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions to restrain T cell–induced B-cell differentiation. These findings shed new light on T cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
Follicular Helper T Cells ; Humoral Immunity ; Primary Immunodeficiencies ; Cytokine Signaling ; Medicine
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