Determinants of antigen specific CD4 T cell function in tuberculosis

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.

Grant Number: 5K08AI150425-05
NIH Institute/Center: NIH
Principal Investigator: Tyler Bold