CD4+ T Cells: guardians of the phagosome

Abstract

CD4(+) T cells are key cells of the adaptive immune system that use T cell antigen receptors to recognize peptides that are generated in endosomes or phagosomes and displayed on the host cell surface bound to major histocompatibility complex molecules. These T cells participate in immune responses that protect hosts from microbes such as Mycobacterium tuberculosis, Cryptococcus neoformans, Leishmania major, and Salmonella enterica, which have evolved to live in the phagosomes of macrophages and dendritic cells. Here, we review studies indicating that CD4(+) T cells control phagosomal infections asymptomatically in most individuals by secreting cytokines that activate the microbicidal activities of infected phagocytes but in a way that inhibits the pathogen but does not eliminate it. Indeed, we make the case that localized, controlled, persistent infection is necessary to maintain large numbers of CD4(+) effector T cells in a state of activation needed to eradicate systemic and more pathogenic forms of the infection. Finally, we posit that current vaccines for phagosomal infections fail because they do not produce this "periodic reminder" form of CD4(+) T cell-mediated immune control.

FIG 1

Early events after a phagosomal infection. The schematic illustrates events occurring at the initial site of infection and a draining lymph node about 1 to 2 weeks after infection.

FIG 2

Events during the persistent phase of a phagosomal infection. The schematic illustrates events at the initial site of infection and a draining lymph node, months after the initial infection.

FIG 3

Events during superinfection of a host with a persistent phagosomal infection. The schematic illustrates events at the indicated sites of a persistently infected host, 1 week after a new infection.