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MOMP T cell epitopes

It is now well established that Th1 cell mediated immune responses to chlamydial infection are protective, both by virtue of providing cognate help for the production of neutralizing antibody and by stimulating the production of chlamydiastatic and immunomodulatory interferon gamma by CD4+ and CD8+ T cells and by NK cells [Johansson et al., 1997]. There are several regions of MOMP (ompA) which are capable of stimulating proliferative CD4+ T cell responses [Allen et al., 1991; Su et al., 1990]. Allen et al., 1991 immunised mice with one of  nine overlapping peptides spanning the entire C. trachomatis ompA protein and found that, although many of the peptides were capable of stimulating proliferative T cell responses, only a single fusion peptide overlapping with VS3 of MOMP elicited T cell help in vivo for the production of high titered antisera which were specific for known protective determinants on MOMP [Allen et al., 1991]. 

The importance of VS3 was further emphasized by Ishizaki et al., 1992 who derived short term T cell lines from Balb / C mice immunised with MOMP and selected with whole organisms. Only a peptide encompassing a conserved region of VS3 elicited a strong proliferative response.  It was concluded that, unlike the response of unselected T cells to several MOMP peptides [Allen et al., 1991],  selection and cloning of short-term T-cell lines restricted the repertoire of antigens capable of being recognized by MOMP-specific T cells [Ishizaki et al., 1992]. By contrast, a different group found that A/J mice primed with synthetic peptides A-8 (amino acids 106 - 130) or A-23 (residues 331 - 355) best provided cognate help for the production of antibody to known ompA neutralizing epitopes in VS1 and VS 4 [Su et al., 1990].  

Using a quite different approach, Stella Knight's group in London presented various MOMP peptides to human dendritic cells, then measured the ability of the antigen-pulsed dendritic cells to stimulate proliferative responses with T cells from naive individuals lacking serological evidence of prior exposure to chlamydial infection. The observed response was antigen dose dependent and had an absolute requirement for dendritic cells as the antigen-presenting cell. Several T cell epitopes were identified, but the most effective at stimulating T cells in the majority [80%] of immunologically naive individuals was a 12 amino acid synthetic peptide which partially spanned the constant region of VS3. FACS analysis showed that both CD4+ and CD8+ T cell populations were stimulated, with production of the known chlamydiastatic and protective cytokine, interferon gamma [Stagg et al., 1993]. Subsequently,  mice were immunised intradermally with the same 12-mer T cell peptide, with serovar F whole organisms or with recombinant MOMP [the skin is a rich source of Langerhans cells of dendritic lineage] and their humoral and cellular immune response was assessed.  Immunized mice showed recall responses to all three chlamydial antigens. T-cell-mediated immunity in the absence of antibody was induced by a single intradermal injection of the peptide together with limited protection against experimental upper female genital tract infection. This confirmed that a primary T-cell epitope identified by in vitro stimulation with dendritic cells could initiate cell-mediated immunity in vivo in mice with a different histocompatability background [Knight et al., 1995].

Since the VS3 region of MOMP contains T cell epitopes important to the known protective Th1 response, it must come under substantial selection pressure. Point mutations within this region are known. In this respect the coevolution of host and parasite [chlamydiae]  can be likened to a molecular arms race. However the greatest opportunity for clonal divergence probably comes from recombination events with other chlamydial species rather than from the stepwise accumulation of point mutations. In this respect it is salutary to note that several significant recombination breakpoints have been identified both before and within VS3 [Millman et al., 2001]. 

[MEW] November 2002

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References

Allen, J. E., Locksley, R. M. & Stephens, R. S. (1991). A single peptide from the major outer membrane protein of Chlamydia trachomatis elicits T cell help for the production of antibodies to protective determinants. Journal of  Immunology 147, 674 - 679.

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

Su, H., Morrison, R. P., Watkins, N. G., Caldwell, H. D. (1990). Identification and characterization of T helper cell epitopes of the major outer membrane protein of Chlamydia trachomatis. Journal of Experimental Medicine 172, 203 - 212.

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