The adaptive immune system is crucial in controlling SARS-CoV-2 infection through the coordinated action of B cells (producing antibodies) and T cells with helper (CD4⁺) or killer (CD8⁺) functions (25). In the following paragraph, when phenotypic and functional characteristics are shared between CD4⁺ and CD8⁺ T cell compartments, we refer to T cells; otherwise, we define the T cell subset that is affected.

A key feature of severe COVID-19 is peripheral lymphopenia, which is reverted with disease resolution (26). This change in T cell numbers is accompanied by long-lasting phenotypic changes persisting in the remaining T cells ranging from activated to fully exhausted/dysfunctional phenotypes (27). Almost all COVID-19 patients develop a T cell response, which is more prominent in the CD4⁺ compartment than in the CD8⁺ compartment (28). The number of CD4⁺ T cell clones against SARS-CoV-2 is correlated with the abundance of the structural protein, with Spike [also the target of all available vaccines (29, 30)], M, and Nucleocapsid as the most prominent antigenic targets.

In COVID-19, as in many other viral infections, CD4⁺ T cells are crucial for providing help to CD8⁺ T and B cells (25–27). Further, the absence of a CD4⁺ T cell response has been linked to lethal COVID-19 infection, which underscores the crucial role of these cells (31, 32) to control infection and disease. Acute SARS-CoV-2 infection is characterized by a strong decrease in naïve CD4⁺ T cells, especially in severe cases (33), with an increased frequency of many effector memory cell subsets. PD-1 (Programmed cell death protein 1) upregulation has been found in all subsets of CD4⁺ T cells, with the exception of the naïve compartment, in combination with other exhaustion markers (34, 35), denoting a dysfunctional/exhausted CD4⁺ phenotype in severe cases.

In contrast, CD8⁺ T cells are critical for virus clearance by killing infected cells that present viral antigens by class I MHC (Major histocompatibility complex) molecules. As expected, the expansion of virus-specific CD8⁺ T cells in COVID-19 has been associated with better clinical outcomes (28, 36). Also for CD8⁺ T cells, Spike, followed by M, and Nucleocapsid are the dominant antigens (36–39). Both SARS-CoV-2 specific CD4⁺ and CD8⁺ T cells are already identified in the first few days after symptom onset (40). Peripheral CD8⁺ T cells have cytotoxic function and secrete cytokines (41) with an increased frequency of HLA-DR⁺/CD38⁺ cells, especially in patients progressing to severe disease. At the same time, numerous studies have reported a dysfunctional, exhausted phenotype of the CD8⁺ T cell compartment linked to disease severity (27, 42) and a propensity for apoptosis as indicated by increased levels of TRAIL-receptor (TNF-related apoptosis-inducing ligand receptor) and CASP3 (Caspase 3) (43).

Intriguingly, the characterization of SARS-CoV-2 antigen-specific T cells in the periphery revealed that different epitopes polarize the CD4⁺ T cell response towards distinct outcomes. Anti-spike CD4⁺ T cells mainly show a Tfh phenotype (44) which is contrasted by a Th1/Th17 polarization of M- and Nucleocapsid-specific T cells (44). Interestingly, CD8⁺ T cells specific for M and Nucleocapsid are more polyfunctional than anti-Spike cells, a finding that has not yet sufficiently been considered in vaccine strategies, which currently target only Spike as antigens (29). Of relevance, antigen-specific T cell activation does not seem to be followed by exhaustion during acute infection and convalescence (45).

In mice SARS-CoV-2 induces a robust T cell response where both CD4⁺ and CD8⁺ T cells are important for virus clearance (46, 47). In addition, similarly to humans, the Type I interferon pathway is critical for the generation of robust T cell responses against SARS-CoV-2 infection in the airways of infected mice (47). Even though, none of the animal models could fully recapitulate the severe SARS-CoV-2 phenotype seen in the lung of humans, upregulation of T cell associated and pro-inflammatory cytokines was observed in the lung of SARS-CoV-2 infected K18-hACE2 transgenic mice (expressing the human angiotensin I converting enzyme 2 (ACE2) receptor) (48). In light of the differences between SARS-CoV-2 infection in humans and the current animal models, this review focuses on the reported human phenotypes.

Most measurements of human adaptive immunity are performed in circulating cells because the blood is by far the most accessible tissue to be investigated as a proxy for tissue immune responses. With this mini-review, we do not aim to provide a comprehensive summary of peripheral T cell phenotypes; we will focus instead on the T cell response to SARS-CoV-2 in the lungs, as the immunological profiles in the two tissues differ (49) ( Figure 2 ).

As peripheral lymphopenia was described early on in the pandemic as a hallmark of COVID-19, which also positively correlated with disease severity, the question was whether these cells migrated to the tissue or suffered activation-induced cell death (AICD). Interestingly, early studies on bronchoalveolar lavage (BAL) found an increased number of infiltrating T cells in moderate rather than severe cases, suggesting a protective role of T cells in the lung. In contrast, severe cases displayed massive AICD in the periphery, resulting in a lack of migration of T cells into their infected tissues (50).

Clinically, the lack of tissue-resident T cells in the lungs of severe COVID-19 patients, together with a lack of expanded SARS-CoV-2 specific T cells in favor of a more dysfunctional/exhausted phenotype, seems to be the most widely confirmed phenotype (32, 50, 51).

Liao and colleagues were among the first to describe the phenotype of lung T cells in COVID-19. Apart from the lower number of CD8⁺ cells, they found a higher frequency of proliferating cells in severe compared to moderate disease (50). These cells also expressed cytotoxic genes (GZMA, GZMK, and FASLG) at high levels. In contrast, genes involved in T cell activation, migration, and cytokine secretion were elevated in moderate cases (50). Investigating the clonality of the T cell response, the authors found that moderate cases had a more robust clonal expansion, as well as enriched expression of tissue residency markers (XCL1, CXCR6, and ITGAE). This suggests a more coordinated T cell response in mild/moderate cases that is able to induce a T_rm phenotype potentially beneficial for viral clearance and long-term protection from reinfection (50). These results were also confirmed by an independent report (52), where the authors highlighted that in severe cases, CD4⁺ T cells exhibit a more naïve phenotype (IL7R, CCR7, S1PR1), again pointing towards a dysfunctional T cell responses in severe COVID-19.

While the early reports certainly elucidated important aspects of the pathomechanisms of SARS-CoV-2 infection, the limited number of patients investigated made it challenging to model disease progression over time. In a later study, Wauters and colleagues included more than 30 patients in their single-cell transcriptomic study and inferred activation/differentiation trajectories across cell types and disease severity (51). Here, a more efficient cross-talk between T cells and the lung microenvironment in mild/moderate patients was described, further supporting the notion that the adaptive immune compartment is critical for resolving the disease (51).

In this cohort, the authors identified a moderately increased frequency of MAIT cells (Mucosal-associated invariant T) and a marked increase in T_rm cells in moderate compared to severe cases, consistent with previous observations (51). Further trajectory analysis clarified that CD8⁺ T cells from patients with moderate disease courses were enriched in the T_rm differentiation trajectory, whereas those from severe patients branched into an exhausted phenotype (51). TCR analysis of the CD8⁺ compartment also confirmed previous findings that mild and moderate patients developed clonally expanded, potentially antigen-specific, T_rm populations, supporting a protective role of the antigen-specific T cells in these patients (51).

A similar trajectory analysis in the pulmonary CD4⁺ compartment revealed a strong polarization of helper cells to Th1/Th17 in COVID-19, also denoted by a dysfunctional phenotype (according to gene expression) in severe disease. TCR analysis showed that these cells are enriched for expanded clones most probably specific for SARS-CoV-2 (51).

Despite a clear association between SARS-CoV-2 specific T cell responses and mild and moderate COVID-19, interpretable as a predominantly protective role of the adaptive response in disease progression (53, 54), other reports have pointed towards a dysfunctional response in severe cases (50, 51). For example, a higher activation state in the overall lymphoid compartment was associated with critical COVID-19 disease (55).

Many reports have indicated an intricate relationship between T cell response and local inflammatory environment, pointing toward a different qualitative, rather than quantitative, response in moderate and severe COVID-19. In this context, several groups have reported a potential pathogenic role of the lung T cell response in COVID-19 contributing to organ damage (45, 56, 57) ( Figure 2 ).

Chua and colleagues used single-cell transcriptomics on lung tissue samples to investigate the interaction between immune cells and lung epithelial cells. In line with the potentially pathological role of the T cell response in severe/critical COVID-19, the high immunological interaction between immune cells and epithelium suggested that this intricate interplay could potentially lead to uncontrolled tissue damage (45).

More recent studies addressed whether tissue damage is mediated only by SARS-CoV-2 specific T cells or if other mechanisms are also involved. In a multi-omic study, Bergamaschi and colleagues analyzed a longitudinal cohort of more than 200 patients, where they identified a late-onset and prolonged bystander CD8⁺ T cell response (56). The authors speculated that these cells could migrate to the lung via CXCR3, leading to NKG2D-dependent killing of non-infected lung cells (56, 58).

Furthermore, supporting the direct pathological role of T cells in the lung, we recently identified a population of CD16⁺ T cells both in circulation and in the lung parenchyma (57). We showed how these cells are induced by the inflammatory microenvironment via complement activation and can adopt antibody-dependent cellular cytotoxicity in response to immune complexes similar to innate immune cells, leading to tissue damage via a TCR-independent mechanism (57). The frequency of these cells was also associated with severe disease and was shown to be a strong prognostic marker for disease severity (57).

It is important to acknowledge that all the above-mentioned studies only partially addressed the dynamics of disease progression in the lung due to the clear difficulties in longitudinal sample procurement. The stage at which the protective response diverges into a dysfunctional phenotype is unclear and requires further insights to fully recapitulate the local processes involved.

Taken together, it is established that T cells in the lung have a dual role during COVID-19, with a more coordinated/protective response driving mild/moderate disease and a dysfunctional/tissue-damaging response in severe disease. It is important to note that T cells are not the only immune cell type with a dysfunctional response in severe COVID-19, as especially lung neutrophils (59) and macrophages (60) were shown to contribute to extensive tissue damage and fibrosis.