Thymic activation improves the outcome of COVID-19 patients with severe pneumonia. The
rs2204985
genetic polymorphism within the
TCRA-TCRD
locus, which affects thymic output in healthy individuals, was found here to modify SARS-CoV-2–specific immunity and disease severity in COVID-19 patients with severe pneumonia. Forty patients with severe COVID-19 pneumonia were investigated. The GG genotype at the
rs2204985
locus was associated, independently of age and sex, with stronger and long-lasting anti–SARS-CoV-2 helper and cytotoxic T cell responses 6 months after recovery. The GG genotype was also associated with less severe lung involvement, higher thymic production, and higher counts of blood naïve T lymphocytes, including recent thymic emigrants, and a larger population of activated stem cell memory CD4
+
T cells. Overall, GG patients developed a more robust and sustained immunity to SARS-CoV-2. Polymorphism at
rs2204985
locus should be considered as an additional predictive marker of anti–SARS-CoV-2 immune response.