Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity;this is the focus of the current proposal. We show here that vaccine-induced memory to Mycobacterium tuberculosis (Mtb) can limit bacterial growth but that under conditions that mimic a natural exposure, the expression of memory Is delayed. Crucially, this delay allows bacterial growth to occur. This growth results in inflammation and the alteration of the environment in which the memory response is expressed. Based on our published and preliminary data we propose the following: Appropriate vaccination induces a population of surveillance cells that populate the lung. These cells respond to infection by initiating IL-17 release and subsequent chemokine induction, which recruits effector IFN-y producing memory cells capable of stopping bacterial growth. To improve vaccination we need to determine how to generate a memory response that can respond rapidly to Mtb infection in the lung and we need to identify a population of cells capable of not only stopping bacterial growth but capable of killing bacteria in the lung. In this new application therefore we want to address two related issues using our working model as a base. The first is the determination of the factors regulating the induction and function of the memory T cell response to TB in the lung (Aim One). The second is the identification of crucial functional attributes of the effector cells capable of mediating immunity to Mtb challenge in the lung (Aim Two). In this new submission we will utilize Mtb-specific TcRTg mice, cytokine- reporter mice and tetramer reagents to analyze antigen-specific responding cells. We will also utilize a proven cell transfer model to investigate the ability of defined subsets of T cell to mediate protection against pulmonary challenge with Mtb. In conjunction with Project 1 we will identify the factors regulating CD4 T cell subsets as well as determining whether novel subsets of cells are active against Mtb. With Project 2 we generate CDS T cell subsets specific for Mtb and determine the ability of these subsets to protect against Mtb. With Project 3 we will determine the ability of selectin-binding activity to identify subsets of cells induced by vaccination and Mtb Infection and determine whether PSGL-1 activity regulates the protective ability of memory T cells.

Public Health Relevance

We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. We will investigate how these cells are regulated and this will have the potential to improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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University of Massachusetts Medical School Worcester
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Bautista, Bianca L; Devarajan, Priyadharshini; McKinstry, K Kai et al. (2016) Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory. J Immunol 197:3936-3949
Strutt, Tara M; McKinstry, Karl Kai; Kuang, Yi et al. (2016) Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza. J Immunol 197:3260-3270
Tinoco, Roberto; Carrette, Florent; Barraza, Monique L et al. (2016) PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion. Immunity 44:1190-203
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Torrado, Egidio; Fountain, Jeffrey J; Liao, Mingfeng et al. (2015) Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. J Exp Med 212:1449-63
Cooper, Andrea M (2015) Mouse model of tuberculosis. Cold Spring Harb Perspect Med 5:a018556
Cruz, Andrea; Torrado, Egídio; Carmona, Jenny et al. (2015) BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4⁺IL-17⁺TNF⁺IL-2⁺ T cells. Vaccine 33:85-91
Sell, Stewart; Guest, Ian; McKinstry, K Kai et al. (2014) Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunol 27:484-96
McKinstry, K Kai; Strutt, Tara M; Bautista, Bianca et al. (2014) Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nat Commun 5:5377
Jain, Nitya; Miu, Bing; Jiang, Jian-kang et al. (2013) CD28 and ITK signals regulate autoreactive T cell trafficking. Nat Med 19:1632-7

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