The adaptive immune response to mucosal pathogens is still poorly understood, limiting the development of new vaccines for important human pathogens such as the category B bioterrorism agent Salmonella. We propose to use newly developed reagents to examine the priming of Salmonella-specific CD4 T cells in the intestinal mucosa and systemic tissues, explore the mechanism of effector cytokine production in the infected liver, and examine the effect of bacteria on the survival of Salmonella- specific T cells in vivo.
The specific aims of this proposal are:
Aim 1. Test the hypothesis that bacterial antigen expression shapes the Salmonella-specific CD4 repertoire at mucosal and systemic sites.
Aim 2. Test the hypothesis that innate activation of Salmonella-specific CD4 T cells amplifies effector cytokine production in infected tissues.
Aim 3. Test the hypothesis that live Salmonella can inhibit survival of activated CD4 T cells via SPI2 effector proteins. Our preliminary data demonstrate that we have identified several new targets of Salmonella-specific CD4 T cells and can develop novel MHC class-II tetramer reagents to track the mucosal and systemic Salmonella-specific T cell response in vivo. Our data also demonstrate that previously activated CD4 T cells can be activated by innate stimuli without TCR ligation. Lastly our preliminary data indicate that live bacteria inhibit the survival of Salmonella-specific T cells in vivo. Our three specific aims will use cutting-edge technology, most of which has been developed by our laboratory during the previous funding cycle, to examine the priming, effector function and survival, of Salmonella-specific CD4 T cells throughout the course of Salmonella infection.

Public Health Relevance

Typhoid is a potentially fatal disease caused by oral Salmonella infection and recognized as a potential bioterrorist threat in the US. This proposal will examine the protective CD4 T cell response to this organism using a mouse model of Salmonella infection and newly developed immunological tools to detect mucosal and systemic responses. This proposal will therefore increase our understanding of how these protective CD4 T cells are activated and function in the face of mucosal bacterial infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Alexander, William A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Atif, Shaikh M; Lee, Seung-Joo; Li, Lin-Xi et al. (2015) Rapid CD4+ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9. Eur J Immunol 45:513-24
Nanton, Minelva R; Lee, Seung-Joo; Atif, Shaikh M et al. (2015) Direct visualization of endogenous Salmonella-specific B cells reveals a marked delay in clonal expansion and germinal center development. Eur J Immunol 45:428-41
O'Donnell, Hope; Pham, Oanh H; Li, Lin-xi et al. (2014) Toll-like receptor and inflammasome signals converge to amplify the innate bactericidal capacity of T helper 1 cells. Immunity 40:213-24
McSorley, Stephen J (2014) Immunity to intestinal pathogens: lessons learned from Salmonella. Immunol Rev 260:168-82
Atif, S M; Uematsu, S; Akira, S et al. (2014) CD103-CD11b+ dendritic cells regulate the sensitivity of CD4 T-cell responses to bacterial flagellin. Mucosal Immunol 7:68-77
Atif, Shaikh M; Winter, Sebastian E; Winter, Maria G et al. (2014) Salmonella enterica serovar Typhi impairs CD4 T cell responses by reducing antigen availability. Infect Immun 82:2247-54
Li, Lin-Xi; McSorley, Stephen J (2013) B cells enhance antigen-specific CD4 T cell priming and prevent bacteria dissemination following Chlamydia muridarum genital tract infection. PLoS Pathog 9:e1003707
Lee, Seung-Joo; Liang, Li; Juarez, Silvia et al. (2012) Identification of a common immune signature in murine and human systemic Salmonellosis. Proc Natl Acad Sci U S A 109:4998-5003
Lee, Seung-Joo; McLachlan, James B; Kurtz, Jonathan R et al. (2012) Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog 8:e1002499
Griffin, Amanda J; McSorley, Stephen J (2011) Generation of Salmonella-specific Th1 cells requires sustained antigen stimulation. Vaccine 29:2697-704

Showing the most recent 10 out of 28 publications