T cell depletion increases humoral response by favoring T follicular helper cells expansion

Antibody‐mediated rejection is a major cause of long‐term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti‐thymocyte globulin (ATG) is a widely used lymphocyte‐depleting induction therapy. However, less is known about how ATG affects Tfh cell development and donor‐specific antibody (DSA) formation. We observed an increase in circulating Tfh cells at 6 months after kidney transplant in patients who received ATG. Using an NP‐OVA immunization model, we found that ATG‐treated mice had a higher percentage of Tfh cells, germinal center B cells, and higher titers of antigen‐specific antibodies compared to controls. ATG‐treated animals had lower levels of IL‐2, a known Bcl‐6 repressor, but higher levels of IL‐21, pSTAT3 and Bcl‐6, favoring Tfh differentiation. In a mouse kidney transplant model, ATG‐treated recipients showed an increase in Tfh cells, DSA and C4d staining in the allograft. Although ATG was effective in depleting T cells, it favored the expansion of Tfh cells following depletion. Concomitant use of IL‐2, tacrolimus, or rapamycin with ATG was essential to control Tfh cell expansion. In summary, ATG depletion favors Tfh expansion, enhancing antibody‐mediated response. In mouse models of immunization and kidney transplantation, ATG treatment alone creates a favorable microenvironment for the generation of T follicular helper cells, leading to higher titers of antigen‐specific antibodies through a mechanism involving low IL‐2 levels.