Ascaris lumbricoides antigen exposure modulates T cell activation via regulation of IL-15Rα expression, STAT5 phosphorylation, and promotes differentiation of BCL6low B cells

Pushpamithran G.; Appelgren D.; Gilman R.H.; Blomgran R. · Frontiers in Immunology (2026) · DOI: 10.3389/fimmu.2026.1766483

Resumen

Background: Mycobacterium tuberculosis (Mtb) causes active tuberculosis (TB) in approximately 10 million people annually, resulting in 1.6 million deaths. TB and helminthiasis have a significant geographical overlap, and helminth infections can trigger immunological responses that dampen Th1 immunity, which is essential for Mtb containment. While B cells are known to modulate T cell responses, their role during helminth/TB co-infection remains unclear. Objective: This study aimed to analyze the effect of helminth exposure on T cell activation in a T and B cell co-culture system. Methods: T and B cells were isolated from healthy donor blood, stimulated with aCD3/aCD28, and exposed to Ascaris lumbricoides protein antigens (ASC) or Schistosoma mansoni soluble egg antigen (SM). Results: B cells reduced T cell proliferation, and SM exposure partly attenuated this inhibitory effect on CD4 T cells. ASC exposure did not affect T cell proliferation but increased soluble IL-15Rα and surface IL-15Rα and IL-2/15Rβ on CD4 T cells. Restimulation with recombinant human IL-15 revealed reduced and unsustained STAT5 activation in CD4 and CD8 T cells in ASC-exposed co-cultures. Additional analysis showed altered phosphorylation of STAT1, STAT3, and STAT6, indicating broader impairment of IL-15 responsiveness and a dampened Th1 activation profile. BCL6/BLIMP-1 transcription factor expression of B cells in ASC-exposed co-cultures suggested a shift toward a more differentiated phenotype, such as plasma cell, memory B cells, or marginal zone MZ B cells, which are all typically BCL6low. The in vivo analysis of peripheral blood mononuclear cells from individuals in a helminth/TB endemic region showed increased frequencies of CD38hiCD24hi B regulatory cells in helminth infected, and MZ B cells (IgMhigh unswitched B cells) in both helminth-infected and helminth/TB co-infected individuals. Conclusion: ASC antigen exposure modulates T cell activation through dynamic regulation of the IL-15-pathway and STAT signaling. These findings suggest that ASC exposure may help prevent prolonged IL-15-driven responses, potentially limiting excessive inflammation during TB. B cells in ASC-exposed co-cultures exhibit transcriptional changes consistent with a shift away from the germinal center phenotype toward more differentiated states. Copyright

Instituciones: Universidad Peruana Cayetano Heredia