**4. CD4 t cell**

CD4 T cells recognize extracellular antigens from proteins endocytosed by APCs and degraded by endosome proteases. During chlamydial infection, APCs such as DCs and macrophages acquire exogenous chlamydial antigens by phagocytizing EBs in the extracellular space or by capturing infected cells harboring RBs. After phagocytosis, APC cleaves chlamydial components and the peptide-MHC II complex is assembled. This complex is then transferred to the cell surface, where it is recognized by the TCR in CD4 T cells [72].

#### *Immune Response to Chlamydia DOI: http://dx.doi.org/10.5772/intechopen.110799*

T cells are detected at the site of infection in mice and humans. The recruitment of CD4 T cells to the infection site occurs by the release of various chemokines as well as the regulation of some surface and adhesion molecules [49, 73–75]. Post-infection APCs also migrate to regions of CD4 T cells. Here, clonal expansion of CD4 T cells recognizing chlamydial antigens is achieved (S. G. [48]).

CD4 T cells play a critical role during chlamydial infection. Evidence from murine non-MHC II models has demonstrated the importance of CD4 T cells in clearing the disease (R. P. [76]). Gondek et al., in their study of murine upper genital *C. trachomatis* infection model studies, suggested that CD4 T cells are necessary and sufficient for clearance of Chlamydia and protection against reinfection [77].

When the cellular immune response against *C. pneumoniae* was examined, proliferation and activation of both CD4 and CD8 T cells were detected during primary infection. However, only the activation of CD4 T cells was detected in the later stage of the infection [78].

CD4 T cells differentiate into subtypes as a result of upregulation of transcription factors that increase the production of specific cytokines after antigen recognition [79]. For example, Th1 cells, which are characterized by the production of large amounts of proinflammatory cytokines, especially IFN-γ, are particularly important for clearance of viral infections and intracellular bacteria [80]. In the context of infection by intracellular bacteria such as Chlamydia, the predominant T cell subset expected to be present is Th1 cells. As stated earlier in the relevant section of this article, Th1 subtype differentiation in CD4+ cells occurs following the production of IFN-γ and IL-12 by innate immune cells early during infection [47, 81].

#### **4.1 T-helper1 responses**

Evidence from mouse models indicates that the Th1 subtype is of particular importance in Chlamydia clearance [48]. Observation of increased susceptibility to chlamydial infection in the absence of IL-12 [82, 83] or IFN-γ receptor [84] emphasizes that IFN-γ-producing CD4 T cells are protective against Chlamydia. However, some evidence suggests that a polyfunctional response involving IFN-γ as well as TNF-α can increase immunity [85].

Th1 cells not only activate phagocytic macrophages, but also direct humoral immunity. At the end of the process in which B cells are activated, Th1-related antibodies such as IgG2a and IgG3 are secreted by plasma cells [25, 86, 87]. In addition, the cytotoxic effect of CD4 T cells has also been demonstrated [84].

Th1 responses against *C. pneumonia* predominate, especially during reinfection. Even in mice genetically predisposed to Th2 responsiveness during primary infection, Th1 responses were elicited during reinfection and increased IFN-γ production [88].

#### **4.2 Other T-helper responses**

Although the predominant CD4 cells are Th1 in chlamydial infection, other T-helper types such as Th2, Th17, Th22, and Th9 have also been detected. However, the role they play during chlamydial infection cannot be definitively determined [80]. For example, the production of IgG1 antibodies is induced by Th2 cells. However, there is evidence that the Th2 response is not protective and even associated with pathology. The Th2 response during human ocular infection has been associated with disease progression and pathology [89]. Transfer of chlamydia-specific Th2 clones

failed to protect mice from genital infection [90]. Another T-helper (Th17) is thought to contribute to the formation of Th1 immunity, but has been associated with both protection and pathogenesis in the mouse model [91, 92].

#### **4.3 Memory CD4 T cells**

Memory CD4 T cells are traditionally grouped into two groups: central memory (Tcm) and effector memory (Tem), while CD4 Tcm cells are primarily found in the circulation and lymphatic tissues; peripheral, non-lymphoid tissues host CD4 Tem cells [93]. Therefore, CD4 Tem cells are thought to play a dominant role in clearing genital chlamydial infections. Recently, it has been discovered that a third subset of memory T cells is important in tissue-specific immune responses. Unlike TEM, which recirculates into the lymphatics and blood after pathogen clearance, these cells that remain in non-lymphoid peripheral tissue after pathogen clearance are called tissue resident memory T cells (Trms). Even in the absence of persistent antigen, Trms persist in peripheral tissues for a long time [93]. These cells are found in epithelial tissues in areas that interface with the environment, such as the gut, lungs, skin, reproductive system [94]. They act as the first line of defense when re-exposure to pathogens. They can respond to pathogenic attack faster than other subsets of memory T cells that need tissue traffic.

During secondary *C. trachomatis* infection in mice, memory T cells coming from the circulation to the upper genital tract mucosa together with the CD4 Trm cells present in the tissues provide optimum clearance. Circulating memory T cells contribute to the clearance of secondary infection. However, it has been shown that they cannot clear secondary *C. trachomatis* infection alone without Trm cells [95]. Studies have shown that memory T cells proliferate more rapidly in response to antigen during secondary infection [8, 96].
