Not just the help The labyrinthine ways of human CD4⁺ T cells

Current vaccine strategies and cancer immunotherapies rely heavily on the induction of cytotoxic CD8⁺ T cells. CD4⁺ T cell help is required for optimal CD8⁺ T cell responses. Whether CD4⁺ T cells have a similar role in human tissues and cancer requires further investigation. In this thesis, we focused on the characterization of less conventional functions of human CD4⁺ T cells in different tissue compartments and cancer. Transcription factor Hobit identifies cytotoxic CD4⁺ T cells that arise during primary hCMV infection. We further defined the core signature of human lung CD4⁺ T_RM, which display properties of CD8⁺ T_RM and have a fast and polyfunctional recall response. Lung CD4⁺ T_RM localize in heterogeneous patterns and consist of distinct subsets of T_H1 and T_H17 T_RM, recognizing numerous pathogens. NSCLC tumors also contain polyfunctional pathogen-specific CD4⁺ TILs with a residency phenotype and PD-1 expression distinguishes functionally distinct subsets. The abundance of CXCL13⁺CD4⁺ TILs with a residency phenotype, significantly correlates with survival and frequencies of CD8⁺ TIL subsets shown to be enriched for tumor-specificity. This suggests that CXCL13⁺CD4⁺ TILs are important in anti-tumor immunity and reflect a patient’s ability to form an anti-tumor response. CD4⁺ T_RM are also protective against coronaviruses. SARS-CoV-2 elicits a strong T_H1 T cell response. COVID-19 ICU patients develop high antibody titers, but an impaired CD4⁺ T cell response. Furthermore, BALF of these patients contain T cells resembling circulating cells rather than T_RM, suggestive of vascular leakage, altogether indicating misbalanced cellular and humoral responses in patients unable to control SARS-CoV-2 infection. Taken together, our findings shed light on the functionality of CD4⁺ T_RM, which could be targeted in novel vaccine strategies and anti-cancer immunotherapies.