Introduction
Coronavirus disease-19 (COVID-19) is a pulmonic infection disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), featured by high infectivity, acute progression and lacking of effective treatment [1-3]. The ongoing COVID-19 pandemic has more than 756 million infections and over 6.8 million deaths by 17 February, 2023 (http://covid19.who.int/). SARS-CoV-2 infection caused a wide range of clinical manifestations from asymptomatic and mild to severe and critical. The most serious outcome is systemic inflammation and tissue damage, leading to death due to the failure of effective immune responses after SARS-CoV-2 infection. The immune responses to SARS-CoV-2 initiated by innate immunity followed by adaptive immunity, including antigen specific B- and T-cell responses. The coordination of innate and adaptive immune responses is critical for control viral dissemination [4]. Current studies showed the key role of neutralizing antibodies to SARS-CoV-2 produced by B cells in protection from infection [5]. However, the neutralizing antibodies wane relatively rapidly, or appear late and maintain very low level [6-8]. Moreover, the SARS-CoV-2 D614G, Beta/Gamma, Delta, Omicron and variants of concern partly escape neutralizing antibodies [9]. The short-lived protection of humoral responses calls for investigation into the role of T cells which serve as critical node to generate effective cellular immune response and enhance humoral immune responses against virus infection.
CD4+ T and CD8+ T cells are the major subsets of T cell population. Upon SARS-CoV-2 infection, naïve CD4+ T cells differentiate into T helper 1 (Th1) cells which activate other immune cells to promote cell-medicated immune responses, T follicular helper (TFH) cells which help B cells to generate high-affinity antibodies [10], and cytotoxic CD4+ T cells (CD4-CTL) expressing or secreting effector molecules [11]. After activation, CD8+ T cells can directly eliminate the virus-infected cells. Following antigen clearance, expanded populations of virus-specific T cells die by contraction or persist as memory subsets, including central memory (TCM) and effector memory (TEM) cells [12]. SARS-CoV-2 specific blood memory T cells persist for more than 8 months post infection [13, 14]. In addition, other T cell subsets, regulatory T (Treg) cells, natural killer T (NKT) cells, gamma-delta T (γδT) cells and mucosal-associated invariant T (MAIT) cells also play important roles during SARS-CoV-2 infection [15-20]. However, the relationship between disease severity and the host T cell responses is not well discussed.
Single-cell RNA sequencing (scRNA-seq) technology has displayed its unique advantages to explore cellular heterogeneity per se, as well as cellular heterogeneity in response to a viral infection, providing unprecedented opportunities to identify novel players and different status in the context of SARS-CoV-2 infection [21]. During the COVID-19 pandemic, several studies performed scRNA-seq to reveal detailed changes in gene expression in different type of T cells among patients with different clinical manifestations [22-24]. Here we have revealed the heterogeneity of the host T cells, including CD4+ T cells, CD8+ T cells, TFH cells, Treg cells, NKT cells, γδT cells and MAIT cells, in the immune responses of COVID-19 patients, which might provide valuable insights into immunotherapy and vaccine development.