Since its start at the end of 2019, the COVID-19 outbreak has posed significant health risks to the human population, surpassing more than 6.5 million deaths across the world (WHO cumulative data up to Oct 2022). Over the past 3 years, publications regarding coinfection with SARS-CoV-2 and other pathogens, such as viruses, bacteria, and parasites, have been reported. Tissue damage resulting from SARS-CoV-2 includes lung failure [1], brain damage [2], intestinal mucosal damage [3], and cardiovascular disease [4]. Furthermore, in cases when a cytokine storm is present in SARS-CoV-2 infection, coinfection may exacerbate the outcomes of other types of diseases, such as allergy, diabetes, and hypertension.

T cells play a pivotal role during viral infection and immune-related diseases. Due to SARS-CoV-2’s ability to alter the T cell response, it may affect the outcomes of several common pathogenic infections and chronic diseases. In a reported case of HIV coinfection with SARS-CoV-2, depletion of CD4⁺ T cells was observed to affect the patient’s clinical outcome [5]. In other conditions such as TB infection and diabetes, there is an increased risk of severe SARS-CoV-2 due to exacerbation of symptoms [6]. In diabetic patients, the increased clinical risk is positively correlated with SARS-CoV-2 infection [7].

2. SARS-CoV-2 Infection and T Cell Response

Within lethal contagious respiratory viruses, the most prevalent transmission route is an airborne infection [8]. In Figure 1, when the SARS-CoV-2 reaches the lung’s epithelial layer, the spike protein on the viral surface will bind with the ACE2 receptor, accelerating the entry of the virus ^[9][10][9,10]. Fusion of the virus and host cell membrane results in the release of the viral genome [11]. Essential components (including N, S, M, and E proteins) and sub-genomic viral RNA are subsequently generated and assembled to form an intact virus [12]. The newly generated virus is released from the cytoplasm through exocytosis [12] and SARS-CoV-2 will be captured by antigen-presenting cells (APC). Viral antigens are then processed and presented to the T cells ^[13][14][13,14]. Meanwhile, the defense mechanism mediated by T cells with SARS-CoV-2 is different from the antibody-dependent response due to their ability to recognize a broad range of viral epitopes ^[13][15][13,15]. Compared with the common cold, SARS-CoV-2 infection generates a diverse epitope pool and increases the frequency of both viral-epitope-specific CD4⁺ and CD8⁺ T cells among convalescent SARS-CoV-2 patients [13]. In terms of infection, T cells secrete IFNγ, Granzyme B, and TNFα to help eliminate SARS-CoV-2 infected cells [16]. In mild COVID-19 patients, the effector CD4⁺ or CD8⁺ T cells will proliferate and form a defense mechanism during the acute phase [17]. In moderate-symptom patients, the natural killer T cell (NKT) CD160 population responds quickly by direct cytotoxicity [18]. Furthermore, the SARS-CoV-2-specific memory T cells are beneficial for providing essential protection against future reinfection ^{[15][19][20][21]}[15,19,20,21].

3. T Cell Subsets and Surface Markers Change during SARS-CoV-2 Infection

As studied, SARS-CoV-2 patients with severe symptoms often displayed progressive lymphopenia, while patients with mild symptoms showed normal absolute lymphocyte counts [22]. Within the CD8⁺ T cell populations in these patients, an increased population of CD8⁺ effector memory T cells was observed [22]. On the other hand, lower CD4⁺ or CD8⁺ frequencies were detected in severe COVID-19 patients compared to mild COVID-19 patients [23]. A study performed by Neidleman et al. indicated that CD27⁺CD28⁺CD8⁺ T effector memory cells re-expressing CD45RA (T_EMRA) were predominant in the recovery period of SARS-CoV-2 patients, contradicting the expression of the CD27 marker [24]. Moreover, there was an increase in both central memory CD8⁺ T cells (CD45RA⁻CD27⁺CCR7⁺) and effector memory CD8⁺ T cells (CD45RA⁻CD27⁺CCR7⁻) ^[25][26][27][25,26,27]. In regards to Ki67⁺ and HLA-DR markers co-expressed on CD8⁺ T cells, SARS-CoV-2 infection led to an increase in Ki67⁺HLA-DR⁺CD8⁺ T cells in the patients [26]. In addition, there was an increase in the expression of activation markers, including HLA-DR and CD45RO, on CD8 T cells in severe SARS-CoV-2 patients compared to mild patients [28]. An increased proportion of CD38^hi+ CD8⁺ T cells was also observed in severe SARS-CoV-2 infected patients ^[26][29][30][26,29,30]. In addition, a reduction in CD27⁺CD8⁺ T cells and an increase in CD127⁺CD8⁺ T cells were found in SARS-CoV-2 patients [24]. When compared to healthy blood donors, CTLA-4, LAG-3, and Tim-3 were significantly expressed in memory CD8⁺ T cells from patients with severe SARS-CoV-2 infection, while there was no difference for the inhibitory immune checkpoint PD-1 marker ^[26][30][26,30]. Cords detected that LAG-3 and TIGIT expression were upregulated in SARS-CoV-2-specific CD4⁺ T cells when compared to CD4⁺ T cells in healthy patients [31]. A higher percentage of cells expressing HLA-DR and CD45RO were also observed within the effector CD4⁺ T cell population in severe patients compared to mild patients [32]. On the other hand, a reduction in CD28⁺CD4⁺ T cells was detected in severe patients compared to mild patients [32]. Cytokines, including IL-2R, IL-6, IL-8, and IL-10, experienced an increase in production from effector CD4⁺ T cells in severe SARS-CoV-2 patients ^[33][34][33,34]. The decreased expression of CD45RA and CCR7 indicated that T central memory cells are more dominant than T effector memory cells [24]. It was also reported that there were high populations of memory CD4⁺ T cells expressing CD38, CD69, Ki-67, and PD-1 in memory CD4⁺ T cells from patients with severe SARS-CoV-2 infection compared to healthy blood donors [26]. Among CD4⁺ T cell subsets, CD4⁺ Teff cells differentiate into functionally diverse subsets such as Th1, Th2, Tfh, Th17, and Treg cells. T helper 1 (Th1) cells protect against intracellular parasites by the secretion of IFNγ ^[35][36][35,36]. Studies have indicated that Th1 cells predominate during SARS-CoV-2 infection through upregulation of IFNγ but not IL-4 or IL-17. T helper 2 (Th2) cells help to eliminate extracellular pathogens [36]. Studies also indicate that Th2 and Th17 cells play a role in SARS-CoV-2 infection in which Th2 cells were claimed to be unfavorable for recovery ^[24][30][37][24,30,37]. Lower levels of Th2 populations were observed in mild patients compared to healthy donors, but no difference was indicated between mild and severe patients. The disproportionate ratio of Th2/Th1 cells revealed a lead in severe infection, with abnormal secretion of associated cytokines such as IL-4, IL-5, IL-10, and IL-13 ^{[30][38][39][40]}[30,38,39,40]. T follicular helper cells (Tfh), a particular subset of CD4⁺ T cells that regulates antibody responses with B cells, have been noted to play a role in SARS-CoV-2 infection [22]. Mathew et al. indicated that there was a decreased population of CD45RA⁻CXCR5⁺PD-1⁺ circulating Tfh (cTfh) cells post-SARS-CoV-2 infection with an upward trend of Tfh cell population in recovered patients within six months [27]. Among cTfh cells, there are multiple subsets including Tfh1, Tfh2, and Tfh17 that are categorized based on differences in the secretion of cytokines. A lower population of cTfh17 (CXCR5⁺CXCR3⁻CCR6⁺) cells, which secrete IL-21 and IL-17A, was discovered in a common variable immunodeficiency disease (CVID) patient with SARS-CoV-2 infection compared to the immunocompetent donor ^[22][41][22,41]. However, for PD-1 marker expression, there were multiple contradictory studies indicating that there were no changes in PD-1⁺ Tfh cells in SARS-CoV-2 patients [42]. A high expression of ICOS was also found in SARS-CoV-2-specific Tfh cells [24]. In regard to Treg cells, which act as suppressors in the immune system, there are conflicting studies. An increased percentage of regulatory T cells (CD3⁺CD4⁺CD25⁺CD127^low) and a higher secretion of IL-10, TGF-b, IL-6, and IL-18 were detected during COVID-19 infection, specifically with N peptide stimulation ^[43][44][43,44]. Increased populations of Treg cells were present in mildly symptomatic patients compared to healthy controls [43].

4. Role of T Cells during Coinfection with Viruses, Bacteria, and Parasites

During the three-year pandemic, researchers have noticed cases of coinfection with SARS-CoV-2 and other viruses (e.g., HBV, HIV, HCV, and influenza), bacteria (e.g., Mtb), and parasites (e.g., protozoa and helminths) (Figure 23).

4.1. T Cells’ Role during SARS-CoV-2 Coinfection with HBV, HIV, HCV, and Influenza

Hepatitis B virus (HBV) is a contagious virus that causes chronic liver diseases such as fibrosis and hepatocellular carcinoma (HCC) ^[45][49]. Currently, the coinfection outcome of SARS-CoV-2 and HBV is still ambiguous. A report displayed that 3% of SARS-CoV-2 patients will suffer from chronic liver disease ^[46][50]. Some researchers reported cases where coinfection resulted in severe liver injury and other severe outcomes ^[47][48][49][51,52,53]. Clinical studies show that coinfected patients experience a high severity and poor prognosis, both of which should be taken seriously ^[50][54]. However, other publications indicate that no significant difference has been observed in the clinical outcome of chronic HBV carriers who were SARS-CoV-2 coinfected ^[51][52][55,56]. On one hand, T cells are important for a host to defend against the invasion of SARS viruses. On the other hand, it is well known that SARS-CoV-2 will induce excessive cytokine storms from T cells, causing increased severity ^[53][57]. In terms of immune suppression by HBV infection, T cell exhaustion is accelerated, and partial cytokine secreted T or NK cells become dysfunctional ^[54][55][58,59]. These counterparts of coinfection may explain the lack of significant difference observed for HBV patients coinfected with SARS-CoV-2 ^[56][60].

4.2. T Cells’ Role during SARS-CoV-2 Coinfection with Mycobacterium tuberculosis (Mtb)

Mycobacterium tuberculosis (Mtb) is an aerobic bacterium that attacks human lung cells ^[57][76]. Although the Bacille Calmette–Guérin (BCG) vaccine is available and provides sufficient protection for infants and children, adults are still vulnerable to infection ^[58][77]. Mtb infection affects the immune system by causing delays in the initial activation of both Mtb-specific CD4⁺ and CD8⁺ T cells ^[59][78]. In a reported study, one article suggests that CD4⁺ T cells may be capable of preventing prevent CD8⁺ T cell exhaustion during Mtb infection ^[60][79]. Since both Mtb and SARS-CoV-2 infections cause damage to lung tissue, coinfection has been associated with a higher death rate compared with SARS-CoV-2 infection only [6]. In coinfection, researchers have discovered that SARS-CoV-2 patients display a decreased frequency of Mtb-specific CD4⁺ T cells ^[61][80]. Furthermore, SARS-CoV-2 patients infected with either TB or latent TB showed a lower response to SARS-CoV-2 and had a decreased Mtb-specific immune response ^[62][81].

4.3. T Cells’ Role during SARS-CoV-2 Coinfection with Parasite

Parasite infection is a long-standing area of concern in the field of public health. In response to common parasitic infections, such as protozoa and helminths, the body will induce regulatory T cells to suppress the host’s antiparasitic immune system ^[63][82]. Multiple researchers have discovered that intestinal parasite coinfection with SARS-CoV-2 decreases SARS-CoV-2-mediated intestinal inflammation risk ^[64][83]. In addition, parasite-driven Th2 and Treg cell responses were able to counterbalance SARS-CoV-2-induced cytokine storms ^[64][65][83,84]. This discovery may explain why parasite coinfection with SARS-CoV-2 may ameliorate the severity of SARS-CoV-2 patients.