Beyond B cell helpers: diverse roles of peripheral helper T cells.

Peripheral helper T cells (TPH cells) constitute a subset of CD4+ T cells that provide help to B cells in inflamed non-lymphoid tissues. TPH cells have been identified across various chronic disorders, especially autoimmune diseases, and accumulating evidence suggests their involvement in disease pathogenesis. However, the mechanisms by which TPH cells drive persistent inflammation remain incompletely understood. Recent insights reveal that TPH cells play additional roles in local immune responses beyond their classical B cell helper function. In this review, we explore the heterogeneity and functional diversity of TPH cells that contribute to chronic inflammatory processes within target tissues of autoimmunity. These functions of TPH cells include their stem-like capacity to serve as a reservoir and replenish activated cells in situ, as well as their direct role in the activation of macrophages through proinflammatory soluble factors. We further discuss the dynamic interplay between TPH cells and tertiary lymphoid structures (TLSs), highlighting the chemokine regulation for TLS formation and the essential niche these structures offer for the TPH cell maturation. A deeper understanding of TPH cell-mediated tissue inflammation will pave the way for the development of novel therapeutic strategies in persistent autoimmune conditions.