This was similarly demonstrated in an HLA-A*11 Vietnamese cohort of DENV-infected patients. It has been proposed that in some cases unfavorable disease results may be caused by lower avidity cross-reactive memory space T cells generated during a main flavivirus illness that preferentially increase Rabbit Polyclonal to JAB1 during a secondary heterologous illness and function sub optimally against the new pathogen. While in additional cases, these cross-reactive cells still have the potential to facilitate cross-protection. With this review, we focus on cross-reactive T cell reactions to flaviviruses and the ideas and effects of T cell cross-reactivity, with particular emphasis linking data generated using murine models to our fresh understanding of disease results following heterologous flavivirus illness. and models that cross-reactive antibodies present at sub-neutralizing concentrations can promote DENV uptake into Fc-bearing cells leading to enhanced viral lots (37, 70C73). However, owing to the fact that DHF happens the maximum of DENV viremia and closer to the maximum in the T cell response, cross-reactive T cells have also been proposed to play a role in the pathology observed (20). It is important to consider that during a homologous secondary illness, the type-specific neutralizing antibody response functions to restrict the replication of computer virus, in effect decreasing the antigenic weight during T cell priming. As a result, the boosted memory space T cell response elicited may only be of moderate size as this is dependent upon antigenic weight. However, inside a heterologous illness, the second illness may not be constrained by cross-reactive neutralizing antibody reactions, and in the case of DENV, cross-reactive antibodies may even enhance the viral weight (74). The large antigen weight could drive a massive growth of cross-reactive memory space T cells, potentially leading to immune-mediated pathology, which is definitely one hypothesis for the pathology observed during DHF (20). In humans, DHF correlates with the magnitude of the T cell response and production of several cytokines, such as TNF-, further providing a means for T cell cross-reactivity to play a role in disease severity (75). In addition to modified cytokine profiles during DHF, modified TCR avidities as a consequence prior DENV exposure have also been reported in humans. For example, in an analysis of a Thai cohort of DHF individuals, it has been demonstrated the humans expressing HLA-A*11 possessed CD8+ T cells reactive to the NS3 epitope (NS3133) present in multiple DENV serotypes (75). LY2365109 hydrochloride While those LY2365109 hydrochloride T cells could bind tetramers comprising peptide variants from multiple DENV serotypes, the avidity with which they did so varied based on the individual’s serotype illness history, specifically with the lowest avidity attributed to the currently infecting serotype (76, 77). This observation helps the OAS hypothesis that cross-reactive cells of lower avidity are maintained in memory space from a prior illness, then increase upon heterologous challenge, which yields T cell populations of lower avidity to the newly infecting serotype (76, 77). This was similarly shown in an HLA-A*11 Vietnamese cohort of DENV-infected individuals. In addition to these modified avidities, modified cytokine profiles LY2365109 hydrochloride in reactions to the same cross-reactive variant peptide ligand as LY2365109 hydrochloride a consequence of secondary heterologous illness were also observed (78). In this case, the result of heterologous secondary illness was a skewing to the production of inflammatory cytokines TNF- and CCL4 with decreased production of IFN- and IL-2 (78C80). This data helps the idea that T cell function can be impacted as a result of cross-reactive DENV illness in humans. Animal Models Of T Cell Cross-Reactivity T cell cross-reactivity reshapes the pathogen specific T cell populace. Exposure to a heterologous challenge alters the practical profile of a cross-reactive T cell relative to T cells that had not seen a heterologous challenge by: (1) altering practical avidity (27, 65, 76, 77), (2) skewing the immunodominance hierarchy (5, 62C66), (3) deviation of cytokine profiles (81C83), and (4) altering memory space populations (64, 76, 84, 85). Cross-reactive T cells can travel the generation of viral escape mutants, which would not be observed in the absence of heterologous challenge (62, 86, 87). As T cell cross-reactivity can have a profound impact on safety and disease (20, 35, 36, 88, 89), it is critically important to understand how and when T cell cross-reactivity can occur and the implications of a cross-reactive T cell response. Lessons From Non-flaviviral Pathogens Much of what we know about T cell cross-reactivity comes from the lymphocytic choriomeningitis computer virus (LCMV), with studies including T cell cross-reactivity between flaviviruses coming to the forefront more recently. This has been eloquently demonstrated in mouse models of T cell cross-reactivity between LCMV and Pichinde computer virus (PV). The immunodominance hierarchy of the T cell response to LCMV in C57BL/6 mice is definitely predictable and stable, with.