A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

Abstract

Chlamydia is responsible for millions of new infections annually, and current efforts focus on understanding cellular immunity for targeted vaccine development. The Chlamydia-specific CD4 T cell response is characterized by the production of IFNγ, and polyfunctional Th1 responses are associated with enhanced protection. A major limitation in studying these responses is the paucity of tools available for detection, quantification, and characterization of polyfunctional, antigen-specific T cells. We addressed this problem by developing a TCR transgenic mouse with CD4 T cells that respond to a common antigen in Chlamydia muridarum and Chlamydia trachomatis. Using an adoptive transfer approach, we show that naïve transgenic CD4 T cells become activated, proliferate, migrate to the infected tissue, and acquire a polyfunctional Th1 phenotype in infected mice. Polyfunctional Tg Th1 effectors demonstrated enhanced IFNγ production compared to polyclonal cells, protected immune deficient mice against lethality, mediated bacterial clearance, and orchestrated an anamnestic response. Adoptive transfer of Chlamydia-specific CD4 TCR Tg T cells with polyfunctional capacity offers a powerful approach for analysis of protective effector and memory responses against chlamydial infection, and demonstrates that an effective monoclonal CD4 T cell response may successfully guide subunit vaccination strategies.

Gamma Interferon Is Required forChlamydiaClearance but Is Dispensable for T Cell Homing to the Genital Tract

“…4). While this has previously been shown indirectly (8,14,15,22), our use of IFN-␥ Ϫ/Ϫ NR1 T cells confirms the importance of IFN-␥ production during C. trachomatis infection. Interestingly, IFN-␥R Ϫ/Ϫ NR1 T cells were still able to protect mice, suggesting that their ability to produce IFN-␥ was enough to help clear infection.…”

“…Those studies showed that antigen-specific CD8 ϩ T cells do localize in sections of the genital tract containing LCMV, correlating with our findings with C. trachomatis. Given this, it is possible that transgenic CD8 ϩ T cells specific for C. trachomatis protein CrpA (7) or transgenic CD4 ϩ T cells corresponding to C. muridarum (8) would similarly be able to home to the specific sites within the genital tract that contain bacteria. Future work will address whether or not this is an NR1 or transcervical inoculation-specific phenomenon within the context of Chlamydia infection.…”

“…address questions regarding antigen-specific T cells in naive mice (6)(7)(8). We have previously established one such transgenic mouse, denoted the NR1 mouse, in which CD4 ϩ T cells are specific for the C. trachomatis protein Cta1 (6).…”

“…Indeed, it has been shown that IFN-␥ is essential for host clearance of Chlamydia (14)(15)(16)(17)(18)(19). It is thought that antigen-specific CD4 ϩ T cells can help control infection through their production of IFN-␥, as endogenous C. trachomatis-specific CD4 ϩ T cells (14) and transgenic CD4 ϩ T cells corresponding to both C. trachomatis and the mouse-adapted pathogen C. muridarum (8,14,15) have all been shown to produce IFN-␥. However, it is unknown if antigen-specific T cell production or sensing of IFN-␥ is absolutely required for homing to the genital tract or for clearing infection.…”

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge

“…This indicates that establishment of resident T cells from T cells originating from circulation may not be strictly dependent on neither α4 or CD103, but does involve CD69 in agreement with previous studies on CD4 Trm cells in various tissues 46 including the genital tract. 47 Interestingly, our data showed that inhibiting lymphocyte egress from the lymph nodes, including the infectiondraining lymph nodes, resulting in a strong decline in T cell numbers in blood, did not reduce the expansion of T cells in the GT or compromize the protection. This showed that in the first phase of the infection, the Trm cells were sufficient to induce a protective immune response ( Fig.…”