Tumor immune surveillance and cancer immunotherapies are thought to depend on the intratumoral infiltration of activated CD8(+) T cells. Intratumoral CD8(+) T cells are rare and lack activity. IL-10 is thought to contribute to the underlying immune suppressive microenvironment. Defying those expectations we demonstrate that IL-10 induces several essential mechanisms for effective antitumor immune surveillance: infiltration and activation of intratumoral tumor-specific cytotoxic CD8(+) T cells, expression of the Th1 cytokine interferon-γ (IFNγ) and granzymes in CD8(+) T cells, and intratumoral antigen presentation molecules. Consequently, tumor immune surveillance is weakened in mice deficient for IL-10 whereas transgenic overexpression of IL-10 protects mice from carcinogenesis. Treatment with pegylated IL-10 restores tumor-specific intratumoral CD8(+) T cell function and controls tumor growth.
Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression.
Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis (Mtb), but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against Mtb infection. Early production of IL-17 in the lungs following Mtb challenge of mice previously vaccinated with Mtb peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary Mtb infection, with Il10−/− mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated antigen-specific IFN-γ and IL-17A responses, and that this regime gives significantly greater protection against aerogenic Mtb challenge in both susceptible and relatively resistant strains of mice. In Mtb-susceptible CBA/J mice, antibody blockade of IL-10R specifically during BCG vaccination resulted in additional protection against Mtb challenge of greater than 1-Log10 compared to equivalent isotype-treated controls. Protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic Mtb infection, and correlated with enhanced lung Th1 and Th17 responses, and enhanced IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2+CD3— lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.
Resistance or susceptibility of inbred mouse strains to the parasite Leishmania major correlates with CD4+ T cell responses of the Th1 or Th2 subsets, respectively. To evaluate the genetic basis for this difference, resistant B10.D2 mice were backcrossed onto susceptible BALB/c mice for five generations with selection for resistance. Candidate resistance loci were identified by high frequency of heterozygosity in resistant N5 backcross mice. Loci on chromosomes 6, 7, 10, 11, 15, and 16 were associated with resistance, demonstrating the multigenic nature of this phenotype. The presence of all six loci was not necessary to confer resistance and no single locus was required. Rather, a variety of combinations of these loci may be capable of interacting to confer resistance.
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