Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in about 1/100,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and 1/2,500 other individuals, is much more frequent in patients with tuberculosis than in ethnicity-adjusted controls (p = 8.37×10−8, odds ratio = 89.31 [95%CI: 14.7–1,725]). We also show that the frequency of P1104A in Europeans has decreased significantly, from about 9% to 4.2%, over the last 4,000 years, consistent with purging of this variant by endemic tuberculosis. Moreover, we show that catalytically inactive P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Finally, we show that catalytically competent TYK2 is critical for IL-23 but not IL-12 responses, whereas catalytically competent JAK2 is redundant for both. Homozygosity for the P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

The peritoneal cavity (PerC) is a singular compartment where many cell populations reside and interact. Despite the widely adopted experimental approach of intraperitoneal (i.p.) inoculation, little is known about the behavior of the different cell populations within the PerC. To evaluate the dynamics of peritoneal macrophage (MØ) subsets, namely small peritoneal MØ (SPM) and large peritoneal MØ (LPM), in response to infectious stimuli, C57BL/6 mice were injected i.p. with zymosan or Trypanosoma cruzi. These conditions resulted in the marked modification of the PerC myelo-monocytic compartment characterized by the disappearance of LPM and the accumulation of SPM and monocytes. In parallel, adherent cells isolated from stimulated PerC displayed reduced staining for β-galactosidase, a biomarker for senescence. Further, the adherent cells showed increased nitric oxide (NO) and higher frequency of IL-12-producing cells in response to subsequent LPS and IFN-γ stimulation. Among myelo-monocytic cells, SPM rather than LPM or monocytes, appear to be the central effectors of the activated PerC; they display higher phagocytic activity and are the main source of IL-12. Thus, our data provide a first demonstration of the consequences of the dynamics between peritoneal MØ subpopulations by showing that substitution of LPM by a robust SPM and monocytes in response to infectious stimuli greatly improves PerC effector activity.

Probiotic supplementation arises as playing an immune-stimulatory role. High-intensity and -volume exercise can inhibit immune cell function, which threatens athletic performance and recovery. We hypothesized that 30 days of probiotic supplementation could stabilize the immune system of athletes preventing immune suppression after a marathon race. Twenty-seven male marathonists were double-blinded randomly into probiotic (Bifidobacterium-animalis-subsp.-Lactis (10 × 109) and Lactobacillus-Acidophilus (10 × 109) + 5 g of maltodextrin) and placebo (5 g of maltodextrin) group. They received 30 sachets and supplemented 1 portion/day during 30 days before the race. Blood were collected 30 days before (rest), 1 day before (pre), 1 h after (post) and 5 days after the race (recovery). Both chronic and acute exercise modulated a different T lymphocyte population (CD3+CD4−CD8− T-cells), increasing pre-race, decreasing post and returning to rest values at the recovery. The total number of CD8 T cell and the memory subsets statistically decreased only in the placebo group post-race. Pro-inflammatory cytokine production by stimulated lymphocytes decreased in the probiotic group after the supplementation period. 30 days of probiotic supplementation maintained CD8 T cell and effector memory cell population and played an immunomodulatory role in stimulated lymphocytes. Both, training and marathon modulated a non-classical lymphocyte population regardless of probiotic supplementation.

The underlying mechanism by which MyD88 regulates the development of obesity, metainflammation, and insulin resistance (IR) remains unknown. Global deletion of MyD88 in high-fat diet (HFD)-fed mice resulted in increased weight gain, impaired glucose homeostasis, elevated Dectin-1 expression in adipose tissue (AT), and proinflammatory CD11c+ AT macrophages (ATMs). Dectin-1 KO mice were protected from diet-induced obesity (DIO) and IR and had reduced CD11c+ AT macrophages. Dectin-1 antagonist improved glucose homeostasis and decreased CD11c+ AT macrophages in chow- and HFD-fed MyD88 KO mice. Dectin-1 agonist worsened glucose homeostasis in MyD88 KO mice. Dectin-1 expression is increased in AT from obese individuals. Together, our data indicate that Dectin-1 regulates AT inflammation by promoting CD11c+ AT macrophages in the absence of MyD88 and identify a role for Dectin-1 in chronic inflammatory states, such as obesity. This suggests that Dectin-1 may have therapeutic implications as a biomarker for metabolic dysregulation in humans.

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