Many pathogens, such as the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb) are able to establish chronic infections that persist in the face of a persistent immune response. Yet we have little understanding of how immune responses can be maintained to chronic infections over the long-term or the relationship between the magnitude of the immune response and pathogen load. Here we propose to address the basic mechanisms underlying persistent T cell responses using a mouse model of Mtb infection. It has been established that although CD4+ T cells play an instrumental role in the control of Mtb infection in humans and mice, these cells are not able to completely clear the infection, thereby allowing the bacteria to persist in the lung (the bacterial """"""""setpoint""""""""). Our preliminary data show that the T cell response to chronic Mtb infection is dynamic and characterized by rapid and continual CD4+ T cell proliferation and cytokine production. However, we don't know how this robust T cell response is maintained over the long term. In particular, we have very little information on whether the effector T cells continually proliferate or become exhausted, whether resting memory T cell pools are established at sites distal to the infection, or the relative contribution of CD8+ T cells. To address these issues we have developed a T cell receptor (TCR) transgenic mouse specific for an Mtb secreted antigen. We will take advantage of these mice to identify the mechanisms underlying persistent T cell responses and determine how the balance between the T cell response and bacterial setpoint is maintained.
In Aim 1, we will determine how antigen-specific T cell responses are maintained during a persistent Mtb infection characterized by chronic antigen exposure. The basic approach will be to transfer naive transgenic T cells into mice that have been aerosol-infected with Mtb and then track the donor cells by flow cytometry. This will allow us to determine the distribution, longevity, phenotype and function of antigen-specific CD4+ T cells in detail during the course of infection.
In Aim 2, we will determine the extent to which antigen-specific T cells regulate the bacterial setpoint. This will be accomplished by determining the extent to which we can modulate the bacterial load setpoint by altering the number and/or function of antigen-specific CD4+ T cells. In addition, we will determine whether CD4+ T cells are the source of IFN? in regulating the bacterial load setpoint. In parallel, we will also determine the extent to which antigen-specific CD8+ T cells contribute to protective immunity. By precisely defining the contribution of both CD4+ and CD8+ T cells, these studies will have important implications for the development of vaccines that promote enhanced control of Mtb infection. Relevance: Pathogens that mediate chronic infections, such as Mtb, are a major public heath threat. The proposed studies will generate information on the maintenance of protective T cell responses and will facilitate the development of new vaccines and therapies against this class of pathogens.
| Orme, Ian M; Robinson, Richard T; Cooper, Andrea M (2015) The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 16:57-63 |
| Cooper, Andrea M (2014) Mouse model of tuberculosis. Cold Spring Harb Perspect Med 5:a018556 |
| Cooper, Andrea M; Torrado, Egidio (2012) Protection versus pathology in tuberculosis: recent insights. Curr Opin Immunol 24:431-7 |
| Reiley, William W; Wittmer, Susan T; Ryan, Lynn M et al. (2012) Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection. J Immunol 189:4451-8 |
| Kohlmeier, Jacob E; Reiley, William W; Perona-Wright, Georgia et al. (2011) Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection. J Exp Med 208:1621-34 |
| Reiley, William W; Shafiani, Shahin; Wittmer, Susan T et al. (2010) Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A 107:19408-13 |
| Robinson, Richard T; Khader, Shabaana A; Martino, Cynthia A et al. (2010) Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rbeta1 isoform that enhances DC migration. J Exp Med 207:591-605 |
| Khader, Shabaana A; Rangel-Moreno, Javier; Fountain, Jeffrey J et al. (2009) In a murine tuberculosis model, the absence of homeostatic chemokines delays granuloma formation and protective immunity. J Immunol 183:8004-14 |
| Winslow, Gary M; Cooper, Andrea; Reiley, William et al. (2008) Early T-cell responses in tuberculosis immunity. Immunol Rev 225:284-99 |
