Determinants of antigen specific CD4 T cell function in tuberculosis

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This proposal presents a five-year research career development program focused on the study of antigen specific CD4 T cells in tuberculosis (TB), with the long-term goals to reveal new information about immune protection in TB and inform the development of an effective new vaccine for this disease. The candidate is currently an Assistant Professor of Medicine at the University of Minnesota (UMN) in the Division of Infectious Diseases. The outlined proposal builds on the candidate’s previous experience by adding new domains of expertise in advanced T cell immunology, international collaborative patient-oriented research and human immunology, and single cell transcriptomics. The training objectives are represented by the mentorship team of Marc Jenkins and David Boulware, and other key collaborators at UMN. The proposed experimental and didactic work will position the candidate with a unique set of cross-disciplinary skills that will enable his transition to independence as a physician scientist focused on the immunology of TB. A better understanding of the factors that govern CD4 T cell function in TB could help guide the development of vaccine candidates more likely to elicit protective immunity against TB disease. It is becoming clearer that IFN-g secretion is only one protective function of CD4 T cells in TB. The other key effector mechanisms of CD4 T cells in TB are still being defined, and the determinants of these immune functions remain to be fully characterized. The overall scientific objectives of this particular project are to characterize CD4 T cell functions at the site of infection and to define how antigen availability and T cell receptor (TCR)- epitope affinity govern these functions. The premise of this proposal is that effector activity of CD4 T cells at the site of TB infection is determined by characteristics of the Mtb antigen targeted. The central hypotheses are 1) that CD4 T cells with lower affinity TCRs, targeting Mtb antigens with moderate abundance, have more diverse and superior functions, and 2) that antigen specific CD4 T cells at the site of infection perform key effector functions outside the Th1 paradigm. To test these hypotheses, the following aims are proposed: Aim 1: Determine how antigen-intrinsic factors govern CD4 T cell function in TB, and Aim 2: Characterize CD4 T cell function and diversity at the site of human TB infection. To accomplish these aims, innovative approaches are proposed including: modulation of Mtb gene expression in vivo, identification of lower affinity TCRs, and unbiased identification of CD4 T cells that have recently received TCR stimulation in vivo. By pairing these approaches in the mouse model with studies of human T cells from the cerebrospinal fluid of individuals with HIV-associated TB meningitis, using single cell transcriptomic profiling, these studies will characterize how Mtb antigen-intrinsic factors elicit CD4 T cell populations of varying functional capacity and diversity. This K08 project will guide new TB vaccine development and promote the candidate’s transition to independence.