Persistent antigen is essential for sustaining Leishmania major –specific memory CD4 ⁺ T cells and long-term immunity

Memory CD4 + T cells are central to long-term immunity, yet their persistence in the absence of antigen remains controversial. Lifelong immunity following cutaneous leishmaniasis is primarily mediated by CD4 + T cells, but whether persistent parasites are required for sustaining this immunity has not been empirically established. Using a nonpersistent Leishmania major strain ( dhfr-ts –deficient), we demonstrate that loss of antigen leads to a decline in Leishmania -specific CD4 + T cells and susceptibility to reinfection. To elucidate the mechanism, we developed Leishmania phosphoenolpyruvate carboxykinase (PEPCK)-specific CD4 + T cell receptor transgenic (PEG) mice, enabling precise tracking of Leishmania -specific memory CD4 + T cells. Both in vitro and in vivo–generated memory PEG cells progressively declined in the absence of antigen, independent of major histocompatibility complex II expression. Mice infected with PEPCK antigen–deficient L. major failed to sustain recall responses and secondary immunity. These findings in a L. major model system argue that persistent antigen may be indispensable for maintaining memory CD4 + T cells and ensuring durable immunity against chronic infections.