Mycobacterium tuberculosis (Mtb), the focus of this proposal, is a successful human pathogen that subverts and evades host immunity by multiple mechanisms. In response to infection, cells of the innate immune system produce IL-12 and type I interferons (IFN). Interferons are a family of diverse cytokines that have myriad activities in regulating immunity and mediating protection against pathogens. While IL-12 is essential for anti-mycobacterial immunity in both people and rodents, type I IFN is detrimental to host immunity against tuberculosis. Importantly, a """"""""TB signature"""""""" has been defined that distinguishes active TB patients from those latently infected. The signature is dominated by a neutrophil-driven IFN-inducible gene profile. Few components of the immune system adversely affect resistance to Mtb. Why type I IFN should adversely affect immunity to Mtb is unknown and is the focus of this proposal. Type I IFN regulates the activation, expansion, and effector function of NK and CD8+ T cells during acute viral infection. We hypothesize that the detrimental effect of type I IFN on immunity to Mtb is mediated by an inhibitory effect on the T cell response. Strategy. iNKT cells sit at the intersection between the innate and adaptive immunity and share features with both NK cells and conventional T cells. Our data shows that IFN? dramatically inhibits IL-12 and TCR-driven IFN? production by iNKT cells. iNKT cells have an innate capacity to recognize Mtb infected macrophages and restrict bacterial growth. Their antibacterial activity in vitro suggests that they should be beneficial in vivo. However, iNKT cells are dispensable for immunity to Mtb, possibly because they become anergic in vivo. In contrast, their specific activation prolongs survival after Mtb infection.
In Aim 1, we will use macrophages and iNKT cells derived from type I IFN receptor (IFNAR) knockout or WT mice to determine how type I IFN produced by Mtb infected cells affects iNKT cell function.
In Aim 2, we will determine how type I IFN affects T cell immunity to Mtb in vivo. Mixed bone marrow (BM) chimeric mice will be used so that IFNAR-/- and WT T cells, exposed to the same bacterial load and inflammatory milieu, can be studied in parallel. Using these mixed BM chimeric mice, we will determine how type I IFN signaling by T cells affects their expansion, survival and acquisition of effector function during Mtb infection. A different set of mixed chimeric mice will be used to determine whether type I IFN signaling by T cells affects host resistance to Mtb infection. Chimeric mice will be made using 90% TCR?-/- BM and 10% WT or IFNAR-/- BM. Nearly all B cells, macrophages and DC in these mice will express IFNAR;whereas all of the T cells will be WT or IFNAR-/-, respectively. By challenging these chimeric mice with Mtb, we can ascertain whether type I IFN signaling by T cells is required for host resistance. Summary. Our in vitro and in vivo models will determine how type I IFN affects T cell immunity to Mtb. We expect that these experiments will explain why type I IFN is detrimental to the host during chronic TB and may suggest how type I IFN signaling can be manipulated to treat TB, particularly for drug-resistant cases.
Pulmonary tuberculosis, the disease caused by Mycobacterium tuberculosis, is a threat to global health. Infection is usually asymptomatic because the immune system is able to limit bacterial growth. The disease tuberculosis occurs when the immune system is no longer able to contain the infection. This research proposal seeks to determine why type I interferon, a cytokine that is crucial during immunity to many pathogens, is detrimental to host resistance against M. tuberculosis. We hypothesize that type I interferon impairs T cell mediated immunity. We hope by understanding what features of the immune response are detrimental, as well as those that are beneficial, we can better develop interventions, including vaccination and immunomodulation, that will help prevent or treat tuberculosis.
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|Booty, Matthew G; Nunes-Alves, Cláudio; Carpenter, Stephen M et al. (2016) Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis. J Immunol 196:1822-31|
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|Rothchild, Alissa C; Jayaraman, Pushpa; Nunes-Alves, Cláudio et al. (2014) iNKT cell production of GM-CSF controls Mycobacterium tuberculosis. PLoS Pathog 10:e1003805|
|Nunes-Alves, Cláudio; Booty, Matthew G; Carpenter, Stephen M et al. (2014) In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol 12:289-99|
|Tatituri, Raju V V; Watts, Gerald F M; Bhowruth, Veemal et al. (2013) Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc Natl Acad Sci U S A 110:1827-32|