The Chemoattractant Receptor Ebi2 Drives Intranodal Naive CD4+ T Cell Peripheralization to Promote Effective Adaptive Immunity.

Lymph nodes (LNs) play critical roles in adaptive immunity by concentrating in one location the antigens, antigen-presenting cells, and antigen-responsive lymphocytes involved in such responses. Recent studies have revealed nonrandom localization of innate and adaptive immune cells within these organs, suggesting that microanatomical positioning optimizes responses involving sparse cooperating cells. Here, we report that the peripheral localization of LN cDC2 dendritic cells specialized for MHC-II antigen presentation is matched by a similarly biased paracortical distribution of CD4+ T cells directed by the chemoattractant receptor Ebi2. In the absence of Ebi2, CD4+ T cells lose their location bias and are delayed in antigen recognition, proliferative expansion, differentiation, direct effector activity, and provision of help for CD8+ T cell-mediated memory responses, limiting host defense and vaccine responses. These findings demonstrate evolutionary selection for distinct niches within the LN that promote cellular responses, emphasizing the critical link between fine-grained tissue organization and host defense. • Naive CD4+ T cells accumulate at the periphery of the T cell zone near cDC2s • CD4+ T cell-intrinsic Ebi2 expression drives intranodal peripheralization • Intranodal peripheralization ensures a temporal advantage in antigen recognition • Intranodal peripheralization is required for effective cellular immunity Host protection requires timely recognition of antigen by rare antigen-specific lymphocytes. Baptista and colleagues reveal that efficient antigen recognition by naive CD4+ T cells requires intrinsic Ebi2-mediated sensing of oxysterol gradients by promoting the preferential accumulation of these lymphocytes at the periphery of the lymph node paracortical area near cDC2s. [ABSTRACT FROM AUTHOR]