Effective humoral immunity depends on tightly regulated interactions between B cells and CD4+ T-helper subsets across lymphoid and peripheral tissues. In autoimmune diseases, these regulatory checkpoints fail, enabling autoreactive B cells to mature, infiltrate tissues and/or produce pathogenic autoantibodies. Three major CD4+ helper subsets, T follicular helper (TFH), T peripheral helper (TPH), and tissue-resident memory (TRM) cells, play key roles in shaping these responses. TFH cells are defined by CXCR5, PD-1 and BCL6 expression and orchestrate germinal centre (GC) reactions in secondary lymphoid organs (SLOs). TPH cells are part of tertiary lymphoid structures (TLS) and provide potent help to memory and atypical B cells and drive antibody-secreting cell formation within inflamed tissues in autoimmune diseases. CD4+ TRM cells are imprinted by local cues to acquire tissue residency programs characterized by CD69 and CD103. Although not exclusively related to B-cell help, their effector function is key for preventing tissue inflammation, including the onset of organ-specific autoimmune diseases. Notably, CD4+ TRM cells share transcriptional programs with TPH cells as well as circulating precursor T helper subsets such as Th17.1 cells. Understanding the shared and divergent transcriptional, migratory and functional programs of these helper subsets is essential for defining how tissue contexts stimulate pathogenic rather than protective B-cell responses in autoimmunity.
Puijfelik et al. (Mon,) studied this question.