CD4+ T cells play a major role in adaptive immune responses to intracellular and extracellular microbes by regulating the functions of B cells, CD8+ T cells, and phagocytes. However, the prevalence of phagosomal infections caused by Mycobacteria, Salmonella, and Cryptococcus in CD4+ T cell-deficient AIDS patients demonstrates that the most important function of these cells is phagocyte activation. Yet this function is poorly understood, which probably explains why no effective vaccines exist for these pathogens that kill at 2 million people every year. The size of this knowledge gap becomes clear when one considers the odd features of CD4+ T cell-dependent concomitant immunity, which likely operates for all phagosomal infections. IFN-? producing Th1 cells control the infection within phagocytes at the initial site of infection and prevent it from spreading to other parts of he body. Oddly, however, the Th1 cells never eliminate the microbes from the initial site. Indeed, persistent infection at the original site is required for the Th1 cells to eliminate bacteria from other body sites after a second infection. The regulatory mechanisms that allow Th1 cells to control the infection without eliminating it are not understood. In addition, it is not clear why CD4+ T cell memory is not retained if the original infection is eliminated and why persistent infection does not result in T cell exhaustion. We will use a sensitive peptide: major histocompatibility complex II (p:MHCII) tetramer- based cell enrichment method to study the endogenous CD4+ T cell response to a prototypical persistent phagosomal infection caused by ingestion of Salmonella enterica serovar Typhimuruim (ST) bacteria to gain insight into how protective CD4+ T cells are generated and function. We will test our idea that presentation of p: MHCII complexes exclusively by infected phagocytes drives the generation of IFN-?-producing Th1 effector cells without generating B cell-dependent follicular helper T cells. We will explore the possibility that infected phagocytes at the site of initial infection produce IL-10, which limis their capacity to clear their infection and prevents terminal differentiation of the Th1 cells, locking them in a state where they retain the capacity to multiple protective phagocyte-activating cytokines. We will determine whether the persistently infected IL-10-producing phagocytes in the mesenteric lymph nodes also stimulate bursts of proliferation by Th1 memory cells that periodically circulate through this site to maintain a stable and functional protective population. Accomplishing our specific aims with a robust defined in vivo model system could guide vaccine development against this recalcitrant class of pathogens.
This project focuses on a significant lymphocyte population and an important type of intracellular infection for which effective vaccines capable of conferring long-term protection in humans do not exist. The innovative approach described in this application could lead to new principles that could be used to produce the first effective CD4+ T cell-dependent vaccines for persistent bacterial infections of phagocytes that kill millions of people every year.
|Goldberg, Michael F; Roeske, Elizabeth K; Ward, Lauren N et al. (2018) Salmonella Persist in Activated Macrophages in T Cell-Sparse Granulomas but Are Contained by Surrounding CXCR3 Ligand-Positioned Th1 Cells. Immunity 49:1090-1102.e7|
|Kotov, Dmitri I; Kotov, Jessica A; Goldberg, Michael F et al. (2018) Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. J Immunol 200:2004-2012|
|Karunakaran, Karuna P; Yu, Hong; Jiang, Xiaozhou et al. (2017) Identification of MHC-Bound Peptides from Dendritic Cells Infected with Salmonella enterica Strain SL1344: Implications for a Nontyphoidal Salmonella Vaccine. J Proteome Res 16:298-306|
|Nelson, Ryan W; Rajpal, Miriam N; Jenkins, Marc K (2015) The Neonatal CD4+ T Cell Response to a Single Epitope Varies in Genetically Identical Mice. J Immunol 195:2115-21|
|Wüthrich, Marcel; Brandhorst, Tristan T; Sullivan, Thomas D et al. (2015) Calnexin induces expansion of antigen-specific CD4(+) T cells that confer immunity to fungal ascomycetes via conserved epitopes. Cell Host Microbe 17:452-65|
|Yang, Jessica A; Tubo, Noah J; Gearhart, Micah D et al. (2015) Cutting edge: Bcl6-interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function. J Immunol 194:5604-8|
|Nelson, Ryan W; Beisang, Daniel; Tubo, Noah J et al. (2015) T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 42:95-107|
|Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W et al. (2015) Generation of Th17 cells in response to intranasal infection requires TGF-?1 from dendritic cells and IL-6 from CD301b+ dendritic cells. Proc Natl Acad Sci U S A 112:12782-7|
|Tubo, Noah J; Pagán, Antonio J; Taylor, Justin J et al. (2013) Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785-96|
|Nelson, Ryan W; McLachlan, James B; Kurtz, Jonathan R et al. (2013) CD4+ T cell persistence and function after infection are maintained by low-level peptide:MHC class II presentation. J Immunol 190:2828-34|