CD4⁺T Cells: Guardians of the Phagosome

Abstract

SUMMARY 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.

Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

“…ϩ T cells play a critical role in protection against pathogens that reside in phagosomes (1). Herein, we demonstrate that the functional capacity of antigen-specific CD4 ϩ T cells maintained during a persistent phagosomal bacterial infection progressively deteriorates and that transient blockade of signaling through IL-10R during T cell priming early in infection leads to generation and maintenance of superior-quality CD4 ϩ T cells that mediate enhanced secondary recall responses.…”

“…CD4 ϩ T cells recognize peptide-major histocompatibility complex class II (peptide-MHC-II) complexes generated in the phagosomes and presented on the surface by antigen-presenting cells. CD4 ϩ T cells play an important role in protection against intracellular pathogens, such as Ehrlichia, that replicate in the phagosomes of the host cells (1,9,10). CD4 ϩ T cells proliferate and differentiate into Th1 effector cells following phagosomal infection and enhance the microbicidal activity of phagocytes (11).…”

“…everal pathogens, including Ehrlichia, have evolved to survive in the endosomes or phagosomes of the host cells and establish persistent infection (1,2). Ehrlichiae are pathogenic Gram-negative intracellular bacteria that are transmitted by ticks to humans and animals (3).…”

Immunity and Immunopathology in the Tuberculous Granuloma

“…In this model, mycobacterium-specific T cells migrate to the site of infection and interact with infected macrophages through the secretion of cytokines such as IFN-g and TNF that induce granuloma formation while enhancing macrophage microbicidal functions. Whereas IFN-g and TNF can be produced by innate immune cells, T cells are potent producers of these cytokines and have been shown to be critical for controlling mycobacterial infection in animal models and humans (Szabo et al 2003;Al-Muhsen and Casanova 2008;Kwan and Ernst 2011;Philips and Ernst 2012;Tubo and Jenkins 2014). Mice deficient in CD4 þ T cells, IFN-g signaling, or TNF signaling show disorganized macrophage aggregates that become necrotic (Kindler et al 1989;Flynn et al 1993Flynn et al , 1995Bean et al 1999;Caruso et al 1999;Scanga et al 2000;Flynn and Chan 2001;Roach et al 2002;Algood et al 2005;Stenger 2005;Chakravarty et al 2008;Wallis and Schluger 2010).…”

Cutaneous Leishmaniasis: Update on Vaccine Development

“…18 This can be accomplished by having a small population of persistent parasites or by "boosting" several times to maintain protection. [93][94][95] Alternatively, adjuvants need to be added to the vaccine cocktail to elicit the proper immune response.…”