CD4+ T Cells Contain Early Extrapulmonary Tuberculosis (TB) Dissemination and Rapid TB Progression and Sustain Multieffector Functions of CD8+ T and CD3− Lymphocytes: Mechanisms of CD4+ T Cell Immunity

Abstract

The possibility that CD4+ T cells can act as “innate-like” cells to contain very-early M. tuberculosis (Mtb) dissemination and function as master helpers to sustain multiple effector functions of CD8+ T cells and CD3-negative lymphocytes during development of adaptive immunity against primary tuberculosis(TB) has not been demonstrated. We showed that pulmonary Mtb infection of CD4-depleted macaques surprisingly led to very-early extrathoracic Mtb dissemination, whereas CD4 deficiency clearly resulted in rapid TB progression. CD4 depletion during Mtb infection revealed the ability of CD8+ T cells to compensate and rapidly differentiate to Th17-like/Th1-like, and cytotoxic-like effectors, but these effector functions were subsequently unsustainable due to CD4 deficiency. While CD3-negative non-T lymphocytes in presence of CD4+ T cells developed predominant Th22-like and NK-like (perforin production) responses to Mtb infection, CD4 depletion abrogated these Th22-/NK-like effector functions and favored IL-17 production by CD3-negative lymphocytes. CD4-depleted macaques exhibited no or few pulmonary T effector cells constitutively producing IFN-γ, TNFα, IL-17, IL-22, and perforin at the endpoint of more severe TB, but presented pulmonary IL-4+ T effectors. TB granulomas in CD4-depleted macaques contained fewer IL-22+ and perforin+ cells despite presence of IL-17+ and IL-4+ cells. These results implicate previously-unknown “innate-like” ability of CD4+ T cells to contain extrathoracic Mtb dissemination at very early stage. Data also suggest that CD4+ T cells are required to sustain multiple effector functions of CD8+ T cells and CD3-negative lymphocytes and to prevent rapid TB progression during Mtb infection of nonhuman primates.

Innate and Adaptive Cellular Immune Responses toMycobacterium tuberculosisInfection

“…HIV infection induced CD4 T-cell depletion, and mice or nonhuman primates experimentally depleted of CD4 T cells are highly susceptible to Mtb infection (Müller et al 1987;Orme 1988;Leveton et al 1989;Flory et al 1992;Lin et al 2012;Pawlowski et al 2012;Yao et al 2014). Indeed, it is well established that T helper cells are critical for containment of Mtb.…”

Characterization of CD4/CD8+ αβ and Vγ2Vδ2+ T cells in HIV-negative individuals with different Mycobacterium tuberculosis infection statuses

“…In vivo studies in a non-human primate model demonstrated that 19 CD4+ T cells were required to sustain multiple CD8+ T cell and CD3+ lymphocyte 20 effector functions and to prevent rapid TB progression during M.tb infection. CD8 T 21 cells also play a major role in anti-tuberculosis immunity [22,23]. However, the differences in antigen-specific T cells in subjects with different M.tb infection statuses 1 in humans are not clear.…”

“…However, the differences in antigen-specific T cells in subjects with different M.tb infection statuses 1 in humans are not clear. Most studies have focused on differences between active 2 tuberculosis and healthy individuals [23][24][25]. Studies on the distribution of T cell 3 subsets in populations with different M.tb infection statuses were limited [26][27][28].…”

Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4+T Cells

“…Previous studies, using adoptive transfer of immune CD4 ϩ T cells (21,22), specific in vivo antibody depletion of CD4 ϩ T cells in mice (23)(24)(25) or macaques (26,27), and effects of CD4 ϩ T cell depletion due to infection with HIV (28), demonstrate the crucial role of antigen-specific CD4 ϩ T cells in the control of M. tuberculosis infection. Furthermore, a T helper 1 (Th1)-type response and the production of interferon gamma (IFN-␥) have been linked to favorable outcomes of M. tuberculosis infection in animal models and humans (29)(30)(31).…”