title: CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques.
abstract: CD4 T cells are believed to be important in protection against Mycobacterium tuberculosis, but the relative contribution to control of initial or latent infection is not known. Antibody-mediated depletion of CD4 T cells in M. tuberculosis-infected cynomolgus macaques was used to study the role of CD4 T cells during acute and latent infection. Anti-CD4 antibody severely reduced levels of CD4 T cells in blood, airways, and lymph nodes. Increased pathology and bacterial burden were observed in CD4-depleted monkeys during the first 8 weeks of infection compared to controls. CD4-depleted monkeys had greater interferon (IFN)-γ expression and altered expression of CD8 T cell activation markers. During latent infection, CD4 depletion resulted in clinical reactivation in only three of six monkeys. Reactivation was associated with lower CD4 T cells in the hilar lymph nodes. During both acute and latent infection, CD4 depletion was associated with reduced percentages of CXCR3(+) expressing CD8 T cells, reported to be involved in T cell recruitment, regulatory function, and effector and memory T cell maturation. CXCR3(+) CD8 T cells from hilar lymph nodes had more mycobacteria-specific cytokine expression and greater coexpression of multiple cytokines compared to CXCR3(-) CD8 T cells. CD4 T cells are required for protection against acute infection but reactivation from latent infection is dependent on the severity of depletion in the draining lymph nodes. CD4 depletion influences CD8 T cell function. This study has important implications for human HIV-M. tuberculosis coinfection.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.forename: Tara
authors.initials: T
authors.lastname: Rutledge
authors.forename: Angela M
authors.initials: AM
authors.lastname: Green
authors.forename: Matthew
authors.initials: M
authors.lastname: Bigbee
authors.forename: Carl
authors.initials: C
authors.lastname: Fuhrman
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D001769:Blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D055985:Latent Tuberculosis / Q000276:immunology* / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D008252:Macaca fascicularis; D054367:Receptors, CXCR3 / Q000032:analysis; D012137:Respiratory System / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D054367:Receptors, CXCR3