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How chlamydiae thwart the cell mediated immune system

Chlamydial antigen processing by host cells.

It is now well established that interferon gamma (ifng), a product of the Th1-biased cell mediated immune response, plays a key role in host protection against chlamydial infection and infections by other intracellular bacteria. Dendritic cells [see also Knight et al., 1998] also play a key role in eliciting the cellular immune response, by presenting chlamydial proteins to T lymphocytes   of the cell mediated immune system [Knight et al., 1995; Stagg et al., 1993; Su et al., 1998]. Chlamydial antigens processed through dendritic cells produce powerful protective immune responses in the mouse [Su et al., 1998; 2000; Shaw et al., 2001] in conjunction with the appropriate host histocompatibility  antigen .  Dendritic cells therefore provide a convenient experimental model with which to define those chlamydial proteins and the peptides there from which generate protective immunity [Knight et al., 1995; Su et al., 1998]. Using dendritic cells in vitro and in vivo, chlamydial peptides and antigens stimulating protective T cell responses have been identified [Knight et al., 1995]. Consistent with what is known from knock out mice, protection is correlated with the generation of a chlamydia-specific, Th1-type, cell mediated immune response [Shaw et al., 2002; Su et al., 1998; 2000; Lu & Zhong 1999], with ifng one of the key effectors and IL-12 , as promoter of the Th1 responses, a key supportive cytokine   [Lu & Zhong, 1999; Zhang et al., 1999].  The superiority of live chlamydiae over dead organisms or recombinant proteins [Shaw et al., 2002] probably lies in their ability to generate a better proinflammatory (granulocyte colony stimulating factor) and Th1-inducing cytokine  response [Su et al., 1998]. Even a short period of chlamydial replication is sufficient to develop measurable protection in mice [Su et al., 2000]. However dendritic cells pulsed in vitro with recombinant major outer membrane protein responded with IL-12 production and stimulated the secretion of gamma interferon secreting CD4+ cells. However when transferred to naive mice they generated a non protective Th2 response to the major outer membrane protein. Thus, although dendritic cells are crucial to generating the antigen specific cellular immune response, and a useful experimental model, caution is needed as their behaviour in vitro is not necessarily predictive of the immune response generated in vivo [Shaw et al., 2002]. 

Given the central importance of dendritic cells for antigen processing, one group in Cambridge has explored how chlamydiae themselves infect these cells. The entry of C. trachomatis  was mediated by the attachment to heparan sulphates and could be inhibited by heparin. Uptake into dendritic cells was not inhibited micropinocytosis inhibitors. Infection of dendritic cells led to their activation and production of IL-12 [promoting Th1 responses] and TNF-alpha but not IL-10. Following invasion, the chlamydiae were confined to distinct vacuoles which did not develop into characteristic inclusion bodies and which, in the first 48 hours, were negative for Lamp-1 or  MHC class II. Although there was no obvious co-localization between the chlamydial  vacuoles and MHC loading compartments, infected dendritic cells nevertheless efficiently presented chlamydial antigens to CD4⁺ T cells. Infected dendritic cells also enabled the production of  C. trachomatis-specific CD8⁺ T cell clones. The authors considered that much of the controversy concerning the role of cytotoxic CD8+ T cells was primarily because of the practical difficulties of studying cytotoxic T cell responses at the clonal level. The use of dendritic cells as antigen-presenting cells was expected to facilitate investigation of these responses [Matyszak et al., 2002].

Role of CPAF (Chlamydia proteosome-like activity factor) and RFX5

Given the importance of the Th1-biased cellular immune response for protection, it follows that chlamydiae might gain substantial advantage if they could prevent the ifng-stimulated induction of class II host histocompatibility antigens which are crucial to this process.  The observation of Zhong et al., 1999,  that chlamydiae can inhibit the ifng-stimulated expression of class II host histocompatability antigens is thus of major interest. Chlamydial inhibition of class II histocompatibility antigen (MHC II) induction was correlated with the degradation of upstream stimulatory factor-1 (USF-1), a transcription factor required for ifng-mediated induction of MHC II transactivator  (CIITA). It was suggested that this was a novel evasion factor used by chlamydiae to circumvent the class II-mediated cellular immune response [Zhong et al., 1999].   Subsequent studies by the same group found that chlamydiae could also inhibit constitutive or ifng-induce expression of class I histocompatibility antigen (MHC 1) expression, [crucial for cytotoxic T lymphocyte action] by degrading the essential downstream transcription factor RFX5.  A C. trachomatis-specified, lactacystin-inhibitable, protease or proteosome-like activity factor (CPAF) was identified as responsible for RFX5 and USF-1 degradation [Zhong et al., 2000]. The gene for CPAF was subsequently identified and shown to be unique to the chlamydiae [MEW comment: the Chlamydiaceae at least!] among which it is highly conserved [Zhong et al., 2001].  In support of this concept, C. pneumoniae encodes a homologue (CPAFcp) of C. trachomatis CPAF. Recombinant CPAFcp degraded RFX5 in a lactacystin-inhibitible manner. CPAFcp was secreted into host cell cytosol by C. pneumoniae. There was further evidence that  CPAFcp is necessary for the degradation of host transcription factors required for MHC antigen expression.  during C. pneumoniae infection [Fan et al., 2002]. Taken together, this suggests that chlamydiae might escape T lymphocyte immune recognition by degrading host transcription factors required for major histocompatibility complex (MHC) antigen expression [Zhong et al., 2001]. Such a mechanism might contribute to the ability of chlamydiae to cause persisting infection [Fan et al., 2002]. Support for this idea comes from the work of Heuer et al., 2003. In C. pneumoniae VR1310 infection of HEp-2 cells up to 48 hours post infection, CPAF is located in the inclusion lumen or on chlamydiae. However, by 72 hours post infection or later, most of the CPAF is in the cytoplasm of the cells. This translocation correlates in time with the degradation of transcription factor RFX5. In models of persistent infected induced by gamma interferon or iron limitation, the cytoplasmic translocation of CPAF is inhibited. Thus CPAF translocation to the cytoplasm appears a distinct process from CPAF production. Moreover the subcellular localization of CPAF therefore differs in acute and persistent C. pneumoniae infection in HEp-2 cells [Heuer et al., 2003]. CPAF of both C. trachomatis and C. pneumoniae have been identified on proteomic maps and appear to be resistant to degradation by host cells [Shaw A. C. et al., 2002]

[MEW comment: This is first class work. Taken together with the newly discovered chlamydia protein associated with apoptotic death domains and the identification of a cytotoxic chlamydial protein with homology to clostridial cytotoxin B [Belland et al., 2001] powerful new insights have recently been gained into the molecular pathogenesis of chlamydial infection. However much work remains to determine the importance of these mechanisms. The dendritic cell is a powerful new tool,  complementary to DNA-based experimental vaccines, for exploring chlamydial peptides and proteins crucial to the generation of cellular immunity and hypersensitivity].

[MEW] June 2003

See also: Role of CD8+ cytotoxic T cells

NEXT: Immunopathology 

References

Belland, R. J., Scidmore, M. A., Crane, D. D., Hogan, D. M., Whitmire, W., McClarty, G. & Caldwell, H. D. (2001). Chlamydia trachomatis cytotoxicity associated with complete and partial cytotoxin genes. Proceedings of the National Academy of Sciences U S A. 98, 13984 - 13989. Full article

Fan, P., Dong, F., Huang, Y. & Zhong, G. (2002). Chlamydia pneumoniae secretion of a protease-like activity factor for degrading host cell transcription factors is required for major histocompatibility complex antigen expression. Infection and Immunity 70, 345 - 349.

Fan, T., Lu, H., Hu, H., Shi, L., McClarty, G. A., Nance, D. M., Greenberg, A. H. & Zhong, G. (1998). Inhibition of apoptosis in chlamydia-infected cells: blockade of mitochondrial cytochrome c release and caspase activation. Journal of Experimental Medicine 187, 487 - 496. Full article 

Heuer, D., Brinkmann, V., Meyer, T. F. & Szczepek, A. J. (2003). Expression and translocation of chlamydial protease during acute and persistent infection of the epithelial HEp-2 cells with Chlamydophila (Chlamydia) pneumoniae. Cellular Microbiology 5, 315 - 322.

Knight, S. C., Iqball, S., Woods, C., Stagg, A., Ward, M. E. & Tuffrey, M. (1995). A peptide of Chlamydia trachomatis shown to be a primary T-cell epitope in vitro induces cell-mediated immunity in vivo. Immunology 85, 8-15.

Knight, S. C., Iqball, S., Roberts, M. S., Macatonia, S. & Bedford, P. A. (1998). Transfer of antigen between dendritic cells in the stimulation of primary T cell proliferation. European Journal of Immunology 28, 1636 - 1644.

Lu, H. & Zhong, G. (1999). Interleukin-12 production is required for chlamydial antigen-pulsed dendritic cells to induce protection against live Chlamydia trachomatis infection. Infection and Immunity 67, 1763 - 1769. Full article

Matyszak, M. K., Young, J. L. & Gaston, J. S. (2002). Uptake and processing of Chlamydia trachomatis by human dendritic cells. European Journal of Immunology 32, 742 - 751.

Shaw, A. C., Van dahl, B. B., Larsen, M. R., Roepstorff, P., Gevaert, K., Van de kerckhove, J., Christiansen, G. & Birkelund, S. (2002). Characterization of a secreted Chlamydia protease. Cellular Microbiology 4, 411 - 424.

Shaw, J. H., Grund, V. R., Durling, L. & Caldwell, H. D. (2001). Expression of genes encoding Th1 cell-activating cytokines and lymphoid homing chemokines by chlamydia-pulsed dendritic cells correlates with protective immunizing efficacy. Infection and Immunity 69, 4667 - 4672. Full article

Shaw, J., Grund, V., Durling, L., Crane, D., Caldwell, H. D. (2002). Dendritic cells pulsed with a recombinant chlamydial major outer membrane protein antigen elicit a CD4(+) type 2 rather than type 1 immune response that is not protective. Infection and Immunity 70, 1097 - 1105.

Stagg, A. J., Elsley, W. A., Pickett, M. A., Ward, M. E. & Knight, S. C. (1993). Primary human T-cell responses to the major outer membrane protein of Chlamydia trachomatis. Immunology 79, 1 - 9.

Su, H., Messer, R., Whitmire, W., Fischer, E., Portis, J. C. & Caldwell, H. D. (1998). Vaccination against chlamydial genital tract infection after immunization with dendritic cells pulsed ex vivo with nonviable Chlamydiae. Journal of Experimental Medicine 188, 809 - 818. Full article

Su, H., Messer, R., Whitmire, W., Hughes, S. & Caldwell, H. D. (2000). Subclinical chlamydial infection of the female mouse genital tract generates a potent protective immune response: implications for development of live attenuated chlamydial vaccine strains. Infection and Immunity 68, 192 - 196. Full article

Zhang, D., Yang, X., Lu, H., Zhong, G. & Brunham, R, C. (1999). Immunity to Chlamydia trachomatis mouse pneumonitis induced by vaccination with live organisms correlates with early granulocyte-macrophage colony-stimulating factor and interleukin-12 production and with dendritic cell-like maturation. Infection and Immunity 67, 1606 1013. Full article 

Zhong, G., Fan, T. & Liu, L. (1999). Chlamydia inhibits interferon gamma-inducible major histocompatibility complex class II expression by degradation of upstream stimulatory factor 1. Journal of  Experimental Medicine 189, 1931 - 1938. Full article  

Zhong, G., Liu, L., Fan, T., Fan, P. & Ji, H. (2000). Degradation of transcription factor RFX5 during the inhibition of both constitutive and interferon gamma-inducible major histocompatibility complex class I expression in chlamydia-infected cells. Journal of Experimental Medicine 191, 1525 - 1534. Full article 

Zhong, G., Fan, P., Ji, H., Dong, F. & Huang, Y. (2001). Identification of a chlamydial protease-like activity factor responsible for the degradation of host transcription factors. Journal of Experimental Medicine 193, 935 - 942.

NEXT: Immunopathology