Virus-specific T cell responses with paradigm-violating properties

• Applicant: Professor Dr. Hendrik Streeck
• Subject Area: Virology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417113807

Classically, CD8 T cells recognize short peptides (8-11 amino acids) presented by a single HLA class I molecule, while CD4 T cells recognize longer peptides (at least 13 or longer) bound to HLA class II. Only in rare instances in the setting of transplantation and autoimmunity CD8 T cell responses have been observed to be class II restricted or CD4 T cell responses to be class I restricte. A recent report in SIV infection describes unconventional class II-restricted CD8 T cell responses in RhCMV/SIV strain 68-1 vector vaccinated macaques that is involved in the protection from SIV infection. In addition, we found a small percentage of HIV-specific CD8 T cells that were class II restricted in chronic HIV infected individuals. These unusual T cells are able to recognize and lyse infected cells in a comparable manner like the immunodominant HLA class I restricted counterparts. Nevertheless, the role in infection control and mode of induction of such CD8 T cell responses in HIV infection is currently unknown. Moreover, in another preliminary study we found a striking frequency of HIV-specific CD4 T cell responses restricted by HLA class I that did not recognize epitopes in the context of class II. In particular, these responses recognized HIV epitopes that have been previously described to be protective in HIV infection such as HLA-B*57 and HLA-B*27. However, whether these responses also play a dominant role in the control of HIV infection is currently unknown. Moreover, function, phenotype and lineage commitment of CD4 and CD8 T cell responses with such specificity has thus far not been systematically studied. We therefore plan to assess the frequency and contribution of paradigm-violating versus traditional T cell responses to HIV immunopathogenesis and control. We are especially interested in the development of these “mismatched” immune responses and plan to compare acute infected patient samples with chronic infections and assess during which stage of infection these T cell responses occur. Moreover, we will determine how effector functions and cytotoxic capabilities of CD4 as well as CD8 T cells change based on HLA presentation pathways and will address potential particularities in the HLA-TCR interaction that may exist in such settings. Furthermore, we believe that these paradigm-violating T cell responses are not specific to HIV infection and therefore plan to systematically assess presence of such responses in other chronic infections including CMV, HBV, HCV or EBV. Overall, elucidating unusual T cells that violate immunologic paradigms is likely to be important in future vaccine design against viral infections and cancer.

• DFG Programme: Research Grants