IL-10 Overexpression After BCG Vaccination Does Not Impair Control of Mycobacterium tuberculosis Infection

Abstract

Control of tuberculosis depends on the rapid expression of protective CD4+ T-cell responses in the Mycobacterium tuberculosis (Mtb)-infected lungs. We have recently shown that the immunomodulatory cytokine IL-10 acts intrinsically in CD4+ T cells and impairs their parenchymal migratory capacity, thereby preventing control of Mtb infection. Herein, we show that IL-10 overexpression does not impact the protection conferred by the established memory CD4+ T-cell response, as BCG-vaccinated mice overexpressing IL-10 only during Mtb infection display an accelerated, BCG-induced, Ag85b-specific CD4+ T-cell response and control Mtb infection. However, IL-10 inhibits the migration of recently activated ESAT-6-specific CD4+ T cells into the lung parenchyma and impairs the development of ectopic lymphoid structures associated with reduced expression of the chemokine receptors CXCR5 and CCR7. Together, our data support a role for BCG vaccination in preventing the immunosuppressive effects of IL-10 in the fast progression of Mtb infection and may provide valuable insights on the mechanisms contributing to the variable efficacy of BCG vaccination.

IL-27 alters inflammatory cytokine expression and limits protective immunity against Mycobacterium tuberculosis in a neonatal BCG vaccination model

“…Importantly our model involves inbred mice that do not recapitulate the genetic diversity in humans, however, as it has not been examined in an experimental model, heterogeneity in the immune response of neonates as a result of the immaturity of the immune system may translate to variability in protection. Furthermore, while there are countless studies in which mice and even NHPs are vaccinated with BCG as adults, most do not report this extensive variability in protection from Mtb challenge ( 22 – 25 ). This underscores the novelty of our model and the importance of neonatal vaccination to better recapitulate the extensive variability of protection by BCG in humans.…”

Bacillus Calmette–Guérin–induced interleukin‐10 inhibits S100A8/A9 production and hinders development of T helper type 1 memory in mice

“…The immunomodulatory ability of IL‐10 on T cells after BCG immunization and M.tb infection is complicated according to the recent reports [15, 18, 33, 34]. IL‐10 hindered the development of CD4 + TCM cells in the lungs after BCG immunization [18] and impaired parenchymal migratory capacity of CD4 + T cells after M.tb infection [33, 34]. Blockade of IL‐10 signaling by an anti‐IL‐10 receptor antibody after BCG vaccination enhanced the Th1 and Th17 responses against M.tb infection [15, 18].…”

“…IL‐10 is known to inhibit T‐cell responses directly via promoting regulatory T cells [31] or by suppressing the function of APCs [32]. The immunomodulatory ability of IL‐10 on T cells after BCG immunization and M.tb infection is complicated according to the recent reports [15, 18, 33, 34]. IL‐10 hindered the development of CD4 + TCM cells in the lungs after BCG immunization [18] and impaired parenchymal migratory capacity of CD4 + T cells after M.tb infection [33, 34].…”

“…. IL-10 hindered the development of CD4 + TCM cells in the lungs after BCG immunization [18] and impaired parenchymal migratory capacity of CD4 + T cells after M.tb infection [33,34]. Blockade of IL-10 signaling by an anti-IL-10 receptor antibody after BCG vaccination enhanced the Th1 and Th17 responses against M.tb infection [15,18].…”

Percentage and Absolute CD4+ Count and Factors Influencing Their Levels in Tuberculosis Patients in a Tetiary Hospital, Kaduna, Nigeria

“…Polyfunctional CD4+ cell express cytokines which include Interferon gamma (IFN-γ), Tumour necrosis factor alpha (TNF-α) and Interleukin-2 (IL-2) on a single cell. CD4 levels deplete in active tuberculosis but improve with treatment and as the disease progresses [6][7][8][9]. Individuals who have deficient CD4+ T-cells are prone to severe TB disease [6,7].…”