The study here sets out to define the conditions and factors involved in the in vivo and in vitro generation of CD4 cytotoxic T lymphocytes or CD4 CTL, in addition to determining the direct roles for CD4 CTL in vivo in antiviral immunity and immune-induced pathology. Many viruses establish persistent infections, which are mostly innocuous. However, immune control of these chronic viral infections has also been linked with viral-induced autoimmunity whereas in the absence of immune protection as in immune compromised individuals, reactivation of the viruses frequently causes lethal diseases. It is not known which immune cells keep persistent viruses under control or cause immune pathology, but cytolytic CD4 effector cells have been associated with chronic viral infections as well as with viral- induced autoimmunity. However, a direct role for CD4 CTL has not been determined and their specific contributions in health and disease remain unexplored. Recently, we published a study showing that CD4 CTL form a separate effector subset distinct from any CD4 T-helper subtype. We further determined that CD4 CTL are progeny of conventional nave CD4 T cells that functionally reprogram in response to chronic antigen-stimulation such as chronic viral infections, and become MHC class II-restricted CTL. Using a combination of these profound new insights together with sophisticated gain- and loss-of-function approaches, we propose here to test the hypothesis that CD4 CTL play critical roles in controlling chronic viral infection and furthermore, that aberrant regulation of these cells might lead to viral-induced immune pathology and autoimmunity.
The proposal aims to fill up a significant gap in our knowledge on the specific contributions of MHC class II restricted CD4 CTL in protective and pathological immune responses. CD4 CTL were previously classified as functional variants of Th1 cells and therefore they have never been specifically targeted in vivo or in vitro and their possible unique contributions in health and disease remain unexplored. Recently, we identified CD4 CTL as a separate type of CD4 effector cells and using a combination of novel insights and newly generated mouse strains, we propose here, to identify the factors that drive the specific differentiation of CD4 CTL and to evaluate their unique contributions to anti- viral protection and/or viral-induced immune-mediated diseases. Thus, Information gained from this research will directly support the overall NIH mission of developing new knowledge that will help to combat devastating diseases such as infections, inflammatory diseases and cancers.
