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    • MDL800 br Specificity of CD T cells and their

    2022-09-09


    Specificity of CD4 T cells and their role in flavivirus neutralizing antibody responses CD4 T cells recognize peptides that are proteolytically processed from protein antigens and presented by MHC class II molecules on the surface of specialized antigen-presenting cells, such as dendritic cells or B cells (Fig. 1b). Epitopes for CD4 T cells have been identified on both structural and non-structural proteins [[41], [42], [43],45,56,57], and the peptide sequences are generally available in the Immune Epitope Database and Analysis Resource (IEDB) [www.iedb.org]. The essential help for high-affinity antibody production is provided by CD4 T cells through direct interaction with B cells and the recognition of peptides presented by these B cells. In the case of B cells producing flavivirus neutralizing antibodies, such helper epitopes can be derived from the E protein, the major surface protein, which is bound by the B cell receptor, but also from the two other structural proteins that are co-internalized as part of the virus particle. Direct T cell help for B cells producing neutralizing MDL800 is therefore restricted to peptides derived from the viral structural proteins, whereas this helper function can not be mediated by epitopes in non-structural proteins. Studies examining the antigen specificity of CD4 T cell responses in human infection and vaccine recipients demonstrate that all three structural proteins contribute to the response [25,39,40,42,43,46,47,[58], [59], [60], [61]]. The particular epitopes selected from these proteins vary by individual subjects. Analyses of immunodominant epitopes in the context of the known atomic structures, however, demonstrate that CD4 T cell responses are focused to a few epitopes in specific regions of the viral capsid protein and at surface-exposed sites of E [25,58,59] (Fig. 1c). Most interestingly, even distantly related flaviviruses which share only about 40–55% identical amino acids, such as Zika, TBE, and YF viruses show a similar immunodominance pattern [25,58,59]. The factors responsible for directing the CD4 T cell response to similar sites at the virus protein surface in different flaviviruses are unknown, but most likely relate to the structural context of these epitopes and their accessibility during antigen processing [25,58,59,62]. In this regard, flaviviruses provide excellent models for elucidating aspects of CD4 T cell immunity that could be modulated by protein conformation, because high resolution structures are available of both, the virion as well as the envelope proteins [[17], [18], [19], [20], [21], [22],[63], [64], [65], [66], [67]]. Complementary to these studies, considerable advancements have been made in the identification of host genetic factors, such as HLA genes, controlling epitope specificities of CD4 T cell responses. In the case of DEN, there is evidence that the magnitude of certain HLA-restricted epitope responses correlates with protection or with disease susceptibilty [46,68,69]. In addition, sequential immunizations or infections with related flaviviruses may alter the specificity of these responses by triggering pre-existing T cell responses to conserved, cross-reactive epitopes, resembling sequences of the previously encountered virus in a process termed ‘original antigenic sin’ [36,60,[70], [71], [72], [73], [74]]. In the case of DEN, cross-reactive memory T cells may result in enhanced production of inflammatory cytokines (such as TNF) and decreased production of IFN-γ and IL-2, and may contribute to the ‘cytokine storm’ and symptoms of DEN hemorrhagic fever [[70], [71], [72],74,75]. However, other studies showed that T cell cross-reactivity does not always lead to altered cytokine responses, but can be associated with robust T cell responses linked to HLA alleles that correlate with less severe DEN, suggesting that cross-reactive T cells could also contribute to protection [76,77]. Furthermore, it was shown that CD4 T cell clones derived from DEN patients recognize not only DEN epitopes but those from other flaviviruses as well [78]. A recent paper in mice provides evidence that cross-reactivity may contribute to protection even between distantly related flaviviruses, such as DEN, YF and JE viruses [36]. A fundamental knowledge of such influences on immunity is thus important to understand how previous flavivirus encounters, either from natural infection or vaccination, affect immunity and clinical outcome of infection with other flaviviruses.