CD4+ T-cell immunity of SARS-CoV-2 patients determine pneumonia development

Most humans infected with SARS-CoV-2 will recover without developing pneumonia. A few SARS-CoV-2 infected patients, however, develop pneumonia, and occasionally develop cytokine storms. In such cases, it is assumed that there is an inadequate immune response to eliminate viral infected cells and an excessive inappropriate immune response causing organ damage, but little is known about this mechanism. In this study, we used single cell RNA sequencing and mass cytometry to analyze peripheral blood T cells from patients hospitalized with proven COVID-19 infection in order to clarify the differences in host immune status among COVID-19 pneumonia cases, non-pneumonia cases, and healthy controls. The results showed that a specific CD4+ T cell cluster with chemokine receptor expression patterns, CXCR3+CCR4-CCR6+ (Th1/17), was less abundant in COVID-19 pneumonia patients. Interestingly, these CD4+ T-cell clusters were identical to those we have reported to correlate with antitumor immunity and predict programmed cell death (PD)-1 blockade treatment response in lung cancer. The Th1/17 cell percentages had biomarker performance in diagnosing pneumonia cases. In addition, CTLA-4 expression of type17 helper T cells (Th17) and regulatory T cells (Treg) was found to be significantly lower. This indicates that functional suppression of Th17 was less effective and Treg function was impaired in pneumonia cases. These results suggest that imbalance of CD4+ T-cell immunity generates excessive immunity that does not lead to viral eradication. This might be a potential therapeutic target mechanism to prevent severe viral infections. ImportanceIn this observational study, 49 consecutive patients with SARS-CoV-2 infection confirmed by PCR testing and admitted to Saitama Medical University Hospital and Saitama Medical University International Medical Centre between December 4, 2020 and January 17, 2022 were included. Of these 49 patients, 29 were diagnosed with COVID-19 pneumonia by computed tomography (CT) scan (Table 1). The unique CD4+ T-cell immunity with less abundant Th1/17 CD4+ T-cell cluster and low expression of CTLA-4 in Th17 and Treg was consistently found in SARS-CoV-2 pneumonia patients on admission and 1-week of admission. The imbalance of CD4+ T-cell immunity may contribute to develop pneumonia in SARS-CoV-2 virus infected patients by delaying viral clearance and resulting in an excessive immune response. O_TBL View this table: org.highwire.dtl.DTLVardef@1aac015org.highwire.dtl.DTLVardef@128c14dorg.highwire.dtl.DTLVardef@aacabaorg.highwire.dtl.DTLVardef@e39c8eorg.highwire.dtl.DTLVardef@13b439a_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1C_FLOATNO O_TABLECAPTIONPatient demographics C_TABLECAPTION C_TBL