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

Abstract

bFor almost 2 decades, results from Chlamydia pathogenesis investigations have been conceptualized using a cytokine polarization narrative. Recent viral immunity studies identifying protective tissue-resident memory T cells (Trm) suggest an alternative paradigm based on localized immune networks. As Chlamydia vaccines enter the preclinical pipeline and, in the case of an attenuated trachoma vaccine, are given to human subjects, it may be useful to ask whether cytokine polarization is the appropriate framework for understanding and evaluating vaccine efficacy. In this review, we revisit C. trachomatis pathogenesis data from mice and humans using a Trm narrative and note a comfortable concordance with the Chlamydia pathogenesis literature. Chlamydia trachomatis infections of ocular and genital tract mucosal epithelia elicit host responses that include formation of submucosal lymphoid aggregates that persist at the site of infection after infectious bacteria are no longer present. In trachoma, these aggregates, called follicles, are easily visible without magnification on routine physical examination and are used to make the clinical diagnosis. Lymphoid aggregates have also been documented in uterine and cervical samples of women with C. trachomatis genital tract infections and are seen in the C. muridarum mouse model of genital tract infections (detailed below).Investigators have speculated about a role for local lymphoid aggregates in protective immunity to Chlamydia. Most presciently, Morrison and Morrison concluded that the "persistence of CD4ϩ -T-cell clusters long after infection had resolved (day 70) may provide for a readily mobilizable T-cell response by which previously infected animals can quickly respond to and control a secondary infectious challenge" (1). Strikingly, this concept is not featured in working models of Chlamydia immunopathogenesis. Instead, CD4 T cell cytokine polarization (Th1, Th2, Th17, . . .) has served as theoretical scaffolding for describing immunoprotection and immunopathology associated with infection. It is unclear whether cytokine polarization is the appropriate framework for understanding Chlamydia pathogenesis. Recent work in viral pathogenesis has identified semiautonomous tissue-localized lymphoid structures containing memory T cells as being critical for protective antiviral immunity (2, 3). The available data suggest that the tissue-resident memory T cells (Trm) in lymphoid aggregates formed in response to C. trachomatis infection play a central role in protective and pathological immune responses in the eye and genital tract. TISSUE-RESIDENT MEMORY T CELLSTrm were originally described for CD8 T cells in the setting of recurrent herpes simplex virus (HSV) reactivations. HSV infects peripheral sensory nerves at the site of infection and travels in a retrograde manner up nerve axons to set up a latent infection in the associated sensory ganglion. When HSV reactivates due to UV exposure or stress, it travels back down the nerve axon and infects the stromal cells adjacent to...

Chlamydia muridarum Induces Pathology in the Female Upper Genital Tract via Distinct Mechanisms

“…The oviduct dilation (g) and inflammatory infiltration (h) scores were compared between the C57BL/6J and CD8 knockout groups, and both groups of mice developed a severe oviduct pathology. nicity (37,38,45), there is no experimental evidence on whether CD4 ϩ T cells can directly promote chlamydial pathogenicity. In the current study, we have presented experimental data for filling in the gap.…”

Subunit vaccines for the prevention of mucosal infection with Chlamydia trachomatis

“…The findings on tissue-resident memory T cells have provided insight into protective immunity mechanisms to C. trachomatis infection [86]. A vaccine to prevent sexually transmitted C. trachomatis needs to develop tissue-resident memory T cells that are capable of detecting incoming C. trachomatis and mount a robust local immune response to limit the spread of infection.…”

Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory

“…The basic cellular immune responses to Salmonella and Chlamydia infection have been elucidated in mouse models and share common features (32–34). As expected for intracellular bacteria, CD4 Th1 cells that express T-bet and produce IFN-γ are critical for bacterial clearance.…”

“…As noted above, data from parabiosis experiments have shown that nonrecirculating memory cells are critical for protective immunity using a prototype Chlamydia vaccine (49). Thus, noncirculating TRM T cells would seem to be an integral component of protective immunity to secondary infection with Chlamydia (34). Therefore, it seems likely that antibiotic treatment during Chlamydia infection will adversely affect the development of Chlamydia -specific TRM within the reproductive tract, but this issue has yet to be examined experimentally.…”