Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection

Abstract

Mice with disrupted ␤ 2-microglobulin (␤ 2 m ؊/؊), I-A (class II ؊/؊), or CD4 (CD4 ؊/؊) genes were examined for their capacity to resolve Chlamydia trachomatis genital tract infection. C57BL/6 and ␤ 2 m ؊/؊ mice resolved infection similarly and were culture negative by 4 to 5 weeks following infection. Conversely, major histocompatibility complex (MHC) class II ؊/؊ mice failed to resolve infection, and CD4 ؊/؊ mice showed a significant delay (2 weeks). Secondary challenge of C57BL/6, ␤ 2 m ؊/؊ , and CD4 ؊/؊ mice established that acquired protective immunity, which was characterized by an infection of shortened duration and reduced shedding of infectious organisms, developed. Serological analysis of C57BL/6 and ␤ 2 m ؊/؊ mice by enzyme-linked immunosorbent assays revealed no striking differences in the immunoglobulin subclass specificity of the anti-Chlamydia response, although some differences were observed in the magnitude of the immunoglobulin G2a (IgG2a) and IgG2b responses. Class II ؊/؊ mice produced lower-titered serum anti-Chlamydia antibodies of all isotypes. The serum antibody responses of CD4 ؊/؊ mice were similar to those of C57BL/6 mice, except that the anti-Chlamydia IgA response was delayed by approximately 3 weeks. Analysis of vaginal washes for Chlamydiareactive antibodies revealed the presence of IgG2a, IgG2b, and IgA in C57BL/6 and ␤ 2 m ؊/؊ mice and primarily of IgA in CD4 ؊/؊ mice. Vaginal washes from class II ؊/؊ mice were consistently antibody negative. Interestingly, the Chlamydia-specific IgA response in the vaginal washes of CD4 ؊/؊ mice was delayed, but its appearance coincided with decreased shedding of infectious organisms and resolution of infection. Our results demonstrate that MHC class II-restricted T-cell responses are necessary for the development of protective immunity to Chlamydia genital tract infection and that local (vaginal) anti-Chlamydia IgA antibody coincides with the resolution of infection. A substantive role for MHC class I-restricted T-cell responses in protective immunity to Chlamydia genital tract infection was not confirmed.

Immunological memory in B‐cell‐deficient mice conveys long‐lasting protection against genital tract infection with Chlamydia trachomatis by rapid recruitment of T cells

“…56 Although cytotoxicity and CD8 + T cells have been implicated in host protection against chlamydiae and were shown to be IFN-c dependent, 57,58 we and others have failed to demonstrate a reduced ability to develop protection against chlamydiae in CD8-or MHC class I-de®cient mice. 4,5,54 However, the present study does not exclude a role of CD8 + T cells in long-term protection against genital tract infection with C. trachomatis. In addition, it is important to emphasize that other factors in addition to IFN-c, such as tumour necrosis factor-a (TNF-a), may contribute to long-term protection.…”

Tissue-Resident T Cells as the Central Paradigm of Chlamydia Immunity

“…Clinical trachoma isolates (serovars A to C) have nonfunctional tryptophan synthesis operons (52), suggesting that the presence of IFN-␥-induced indoleamine 2,3-dioxygenase (tryptophan starvation defense pathway) is not consequential to Chlamydia replication in the eye. Furthermore, while CD8 T cells are not critical for clearing C. muridarum genital tract infections (53), they appeared to play an important role in protective eye immunity in a nonhuman pri-mate trachoma model (54). Speculation about how c-MLC assemble is beyond the scope of this review, with little published data to inform a discussion.…”

Identification and characterization of novel recombinant vaccine antigens for immunization against genitalChlamydia trachomatis

“…The use of various mouse gene-knockout strains (Cotter et al, 1997;Johansson et al, 1997;Su et al, 1997), in vivo depletion of specific lymphocyte populations, and transfer of immune lymphocyte populations to naïve mice led to the notion that C. trachomatis immunity is mediated by mucosal immunoglobulin A (IgA) antibodies, IgG molecules that transmigrate the gut epithelium, and T-helper type 1 (Th1) CD41 T cells secreting interferon-g (IFN-g) (Cain & Rank, 1995;Morrison et al, 1995;Perry et al, 1997;Igietseme & Murdin, 2000;Morrison & Morrison, 2001;Igietseme et al, 2002;Morrison & Caldwell, 2002;Barr et al, 2005;Brunham & Rey-Ladino, 2005). B-cell-deficient mice are comparable to wild-type mice in overcoming primary infection, suggesting that B cells play only a minor role in preventing an initial infection.…”