p38γ and p38δ support CD4+ T cell responses and T cell-dependent humoral immunity.

p38γ and p38δ (p38γ/p38δ) have emerged as important regulators of immune function; however, their specific contribution to adaptive humoral responses remains poorly understood. Based on previous evidence that global p38γ/p38δ deficiency impairs antibody production, we investigated the T cell-intrinsic role of these kinases using conditional knockout mouse models. T cell-specific combined deletion of p38γ and p38δ altered antigen-specific IgG subclass production in vivo, causing transient reductions in IgG2b and IgG3 and a persistent decrease in IgG2a titres. This defect correlated with impaired activation of CD4+ T cells, reduced generation of effector T cells, and a significant decrease in T follicular helper (Tfh) cell differentiation. Gene expression analyses revealed diminished levels of key Tfh-associated cytokines, including Il21, Il4, Cxcl13, and Il10. Together, these findings demonstrate that p38γ/p38δ signalling in T cells is essential for Tfh differentiation, cytokine production, and effective T cell-dependent humoral immunity, including the generation of class-switched IgG antibodies, particularly IgG2 subclasses.