An Inclusion Membrane Protein from Chlamydia trachomatis Enters the MHC Class I Pathway and Stimulates a CD8+ T Cell Response

Abstract

During its developmental cycle, the intracellular bacterial pathogen Chlamydia trachomatis remains confined within a protective vacuole known as an inclusion. Nevertheless, CD8+ T cells that recognize Chlamydia Ags in the context of MHC class I molecules are primed during infection. MHC class I-restricted presentation of these Ags suggests that these proteins or domains from them have access to the host cell cytoplasm. Chlamydia products with access to the host cell cytoplasm define a subset of molecules uniquely positioned to interface with the intracellular environment during the pathogen’s developmental cycle. In addition to their use as candidate Ags for stimulating CD8+ T cells, these proteins represent novel candidates for therapeutic intervention of infection. In this study, we use C. trachomatis-specific murine T cells and an expression-cloning strategy to show that CT442 from Chlamydia is targeted by CD8+ T cells. CT442, also known as CrpA, is a 15-kDa protein of undefined function that has previously been shown to be associated with the Chlamydia inclusion membrane. We show that: 1) CD8+ T cells specific for an H-2Db-restricted epitope from CrpA are elicited at a significant level (∼4% of splenic CD8+ T cells) in mice in response to infection; 2) the response to this epitope correlates with clearance of the organism from infected mice; and 3) immunization with recombinant vaccinia virus expressing CrpA elicits partial protective immunity to subsequent i.v. challenge with C. trachomatis.

Antigen-Specific CD8+ T Cells Respond to Chlamydia trachomatis in the Genital Mucosa

“…Of the two Ags, CrpA elicits the more dominant CD8 ϩ T cell response following Chlamydia infection. Immunization of mice with recombinant vaccinia expressing CrpA provides immunity against systemic Chlamydia challenge, suggesting that CrpA-specific CD8 ϩ T cells can play a role in limiting infection with C. trachomatis (8).…”

“…These include membrane proteins that lie at the interface between the Chlamydia vacuole and the host cytosol (6). Two of these proteins, Cap1 and CrpA, are recognized by CD8 ϩ T cells following systemic Chlamydia infection (7,8). Of the two Ags, CrpA elicits the more dominant CD8 ϩ T cell response following Chlamydia infection.…”

Immune-mediated control of Chlamydia infection

“…We have recently identified C. trachomatisspecific T-cell epitopes in mice which have allowed us to enumerate T cells specific for a single antigen over the course of infection (Fling et al, 2001;Starnbach et al, 2003). Furthermore, we have generated T-cell receptor (TCR) transgenic and retrogenic mice specific for defined Chlamydia-specific CD4 + and CD8 + T-cell antigens, allowing us to examine the early response of Chlamydiaspecific T cells to cognate antigen .…”

“…These include proteins that are secreted into the cytoplasm (Zhong et al, 2001;Clifton et al, 2004) as well as inclusion membrane proteins that have domains which extend into the cytosol of the host cell (Bannantine et al, 2000;Fling et al, 2001). Chlamydia proteins that have access to the cytosol have been demonstrated to serve as CD8 + T-cell antigens (Fling et al, 2001;Starnbach et al, 2003).…”

“…As a consequence, these CD8 + T cells specific for non-cytosolic antigens may not recognize the typical cell type infected with C. trachomatis, and may therefore not contribute significantly towards containing the infection. The CrpA antigen described above has access to the cytosol (Bannantine et al, 2000), and indeed T cells specific for this antigen are protective (Starnbach et al, 2003;). It will be interesting to determine whether CD8 + T cells specific for antigens that do not have access to the cytosol of host cells can provide protection against Chlamydia infection.…”