Setting Sights on Chlamydia Immunity's Central Paradigm: Can We Hit a Moving Target?

LETTER

Johnson and Brunham's intent to reframe Chlamydia immunity's central paradigm (1) seems especially relevant to vaccine development. While prevailing dogma maintains that Chlamydia vaccines will need to elicit robust, pathogen-specific T_H1-type responses, these authors suggest that proper evaluation of a vaccine's clinical effectiveness requires understanding of protective tissue-resident memory (Trm) T cell immunity. The latter host response is characterized by an expansion and retention of Trm CD4⁺ and CD8⁺ T cells in infected nonlymphoid tissues that is orchestrated by dendritic cells and macrophages (2–4).

Recent efforts to reconceptualize Chlamydia immunity center on the need to better align clinical observations with current understanding of Chlamydia pathogenesis. For example, the T and B cell-enriched lymphoid follicles that persist in Chlamydia-infected genital (5–8) and conjunctival (9–12) tissues resemble the cellular network of lymphocytes and antigen-presenting cells that typify Trm immunity. Johnson and Brunham also suggest that any argument for hegemony of Chlamydia-specific T_H1 immunity is weakened by clinical studies in which enhanced protection from incident genital infection was associated with increased production of the T_H2 cytokine interleukin-13 (IL-13) by peripheral blood mononuclear cells stimulated ex vivo with Chlamydia antigen (13).

It is less certain why these authors further contend that the increased presence of IL-13-secreting T cells in the peripheral blood of protected individuals supports Trm immunity as the new paradigm of Chlamydia host defense. First, Trm T cells are defined as nonrecirculating memory T cells that persist primarily in epithelial barrier tissues (14). There also seem to be no reports in which IL-13-secreting Trm T cells were identified outside the context of host responses polarized toward type 2 immunity (15–17). Therefore, it remains feasible that type 2 immunity, including Trm T cells, is an important element of the human host response to Chlamydia (18).

Supporting this possibility, clinical studies showed that trachoma infection significantly increased conjunctival tissue expression of MMP10, IL-13RA2, MUC5A, CCL11, ARG1, IL-4, and other molecules associated with type 2 immunity (19–22) and that increased expression of IL-13RA2 and ARG1 was associated with enhanced protection (20). Providing further evidence of a role for type 2 immunity in humans, infant lower respiratory tract Chlamydia trachomatis infections were associated with peripheral eosinophilia (23, 24). Likewise, we found that genital Chlamydia infection in women induced dramatic increases in circulating Chlamydia-specific IL-4-secreting CD4⁺ T cells (25). Moreover, this observation was accompanied by responses in infected endometrial tissue that included enrichment of GATA3-expressing CD4⁺ T cells, alternative macrophage activation, and activation of signaling pathways linked with tissue repair (25).

These clinical findings suggest that the central paradigm of Chlamydia immunity remains a moving target and that it will be important to better define the role of type 2 immunity during Chlamydia infection. Notably, as Chlamydia vaccines are entering preclinical pipelines and initial clinical testing, the relevant human host responses to this pathogen are undefined. We suggest that the development of Chlamydia vaccines that are both effective and safe will require the field to become more comfortable with this uncertainty.