Functional cooperation between T helper cell determinants

Abstract

A ssociative recognition is a basic regulatory mechanism of the immune response and refers to the phenomenon in which immunity to one determinant of a multideterminant antigen enhances the response to other determinants. The cooperative effect is mediated by a determinant recognized by T helper cells (Th) and has been demonstrated for B cell responses (T-B cooperation) (1) and cytotoxic T lymphocytes responses (Th-cytotoxic T lymphocyte cooperation) (2). A similar form of associative recognition between two Th cell determinants (Th-Th cooperation) has not been described yet but could prove valuable to responses against poorly immunogenic antigens such as tumor antigens. The immune response against tumor antigens is hindered, among other factors, by down-regulation of MHC molecules, self-tolerance, and functional hierarchy in the immunogenicity of T cell determinants. It is now clear that T cell determinants of protein antigens can be categorized into dominant, subdominant, and cryptic to reflect a different degree of immunogenicity in vivo (3). Consequently, as T cells reactive with dominant determinants of tumor antigens are eliminated in the thymus during negative selection, the adult immune repertoire is composed mainly of precursor cells with moderate avidity for subdominant and cryptic determinants. Thus, methods to heighten the response of CD4 and CD8 T lymphocytes of the residual repertoire against poorly immunogenic determinants are needed to develop better immunogens against cancer.MUC-1, a glycosylated molecule of high molecular weight expressed in malignant tumors of epithelial origin (4, 5), induces both CD8 (6-8) and CD4 T lymphocytes (9, 10) against an antigenic core consisting of a tandem repeat of 20 amino acid residues. For these reasons, MUC-1 is a useful model antigen for targeted manipulations of the immune response. Specific T cell responses against MUC-1 were induced in C57BL͞6 mice using a model of epitope-based genetic vaccination, somatic transgene immunization (11). This approach is based on the inoculation into the spleen of adult mice of plasmid DNA comprising an Ig heavy (H) chain gene controlled by a B cell-specific promoter to target resident B cells (12). The use of Ig genes modified in the complementaritydetermining regions (CDR) to code for heterologous epitopes (13) allows one to direct the in vivo synthesis and secretion by B cells of transgenic Ig, which immunize the host against the B and T cell epitopes expressed in their V region (14,15). Unlike conventional DNA vaccination (16), which induces Th1 responses (17), somatic transgene immunization activates Th0 cells that produce IL-2, IFN-␥, and IL-4 (15). One advantage of somatic transgene immunization is that heterologous epitopes can be assembled on the Ig V region in various assortment and combination to maximize immunogenicity but also to provide easy tools to study the reciprocal regulation between distinct antigenic determinants during the immune response in vivo.Here, we report that an immunologically silent Th cell d...

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…The addition of canarypox expressing CD40L had not only increased specific CD8 + T cell responses qualitatively but also improved the quality of CD8 + T cells as exhibited by more specific polyfunctional CD8 + T cells and potentially more long lived memory CD8 + T cells as determined by IL-7Rα staining. Some previous reports suggested that CD40L is also important for enhancing CD4 + T cell responses [56][57][58]. Our data are consistent with these reports in that the CD40L regimens enhanced splenocyte proliferation and Th1 cytokine production to vaccine antigens, however, only when CD40L was expressed as a membrane molecule in canarypox vector.…”

CD8 T cell priming by B lymphocytes is CD4 help dependent

“…B7, ICAM-1 and CD44H). This is also consistent with the fact that the ThTh cooperation triggered by an antigen-presenting B lymphocyte is regulated by CD40 and OX-40 [26]. The up-regulation of CD40 in B lymphocytes can result either from CD40L on activated T cells or from B lymphocytes soliciting their own help from CD4 T cells [27].…”

Genetic immunization with a melanocytic self-antigen linked to foreign helper sequences breaks tolerance and induces autoimmunity and tumor immunity

“…Such a strategy has been successfully employed for the induction of autoantibodies against the self-proteins ubiquitin and TNF␣ using an E. coli-derived recombinant protein which had been genetically engineered to contain a known immunogenic T-helper epitope derived from a foreign antigen within its sequence. 17,18 In conclusion, we show that a genetic melanoma vaccine consisting of an immunogenic foreign helper sequence linked to a melanocytic self-antigen is able to break peripheral T cell tolerance and induce protective immunity against B16 melanoma in C57BL/6 mice. Most importantly, these results provide the scientific basis for the exploration of similar antigen-specific immunization strategies in future clinical trials for the immunotherapy of melanoma.…”