Updated Insights into the T Cell-Mediated Immune Response against SARS-CoV-2: A Step towards Efficient and Reliable Vaccines

SARS-CoV-2 has evolved into variants (notably Omicron and its sublineages) with increased resistance to neutralizing antibodies elicited by infection or vaccination. Given rapid viral evolution, cell-mediated (T cell) immunity is crucial for infection control and favorable outcomes. Robust T cell responses correlate with milder disease, though hyperactivation may worsen pathology. T cells target conserved epitopes, enabling cross-recognition of variants such as Delta and Omicron. Early cytotoxic CD8+ T cell responses support viral clearance and mild disease, including bystander activation roles. Cross-reactive T cells from prior endemic coronavirus exposure may modulate disease, especially in younger individuals, although cross-reactivity can be impaired for mutated epitopes in some VOCs. Mechanistically, SARS-CoV-2 antigens are processed by APCs and presented via MHC to CD4+ and CD8+ T cells, driving B cell help and cytotoxic killing. Regulatory T cells may influence immunopathology, but their role remains unclear. Vaccination induces durable T cell responses detectable up to 6 months and reactive to variants, potentially compensating for reduced neutralizing antibodies. The review examines how T cell responses shape infection outcomes, the impact of variants, T cell exhaustion, and therapeutic strategies to modulate T cell immunity.

- Severe COVID-19 associates with cytokine storms (elevated IL-1, IL-2, IL-6, IL-7, IL-8, IL-10, G-CSF, TNF-α) and profound lymphopenia; high IL-6 correlates with T cell depletion and lymph node/splenic pathology. - T cell counts inversely correlate with disease severity and mortality; earlier IFN-γ-secreting T cell responses predict favorable outcomes; convalescence features T cell expansion and SARS-CoV-2-specific clonotypes. - Severe disease shows dysregulated immune activation with prominent myeloid-driven lung inflammation; higher lung T cell frequencies correlate with survival, whereas higher myeloid infiltration correlates with death. - Th1-polarized responses with IL-10 production can control virus while limiting pathology; in severe COVID-19 this switch appears impaired and may relate to vitamin D pathways. - Vaccine-elicited T cells: mRNA-1273 and BNT162b2 induce Th1-biased CD4+ and measurable CD8+ responses with minimal Th2; adenoviral and DNA platforms also induce Th1-biased T cells. T cell responses appear by day 7, peak around days 14–28, and persist for months. - Variant impact: Despite extensive Spike mutations, most T cell epitopes are conserved—about 93% of CD4+ and 97% of CD8+ epitopes remained conserved across variants in studied cohorts. Vaccine-induced T cell responses largely retain reactivity to Delta and Omicron; Omicron-specific CD8+ T cells were detected in ~63% of vaccinees in one study, with CD4+ responses >90% after primary series. - Breakthrough infections after boosters show augmented T cell responses to Omicron Spike; a minority (~15%) showed decreased CD8+ responses over time, supporting booster strategies in vulnerable groups. - T cell exhaustion in severe disease is characterized by increased inhibitory receptors (PD-1, TIM-3, CTLA-4, TIGIT, CD39) and reduced cytokine polyfunctionality; elevated IL-10 may drive exhaustion. However, PD-1 expression alone does not equal functional exhaustion; PD-1+ SARS-CoV-2-specific CD8+ T cells can remain functional in some studies, highlighting heterogeneity. - Immunomodulatory strategies: IL-6R blockers (e.g., tocilizumab), TNF inhibitors, JAK inhibitors (e.g., ruxolitinib) can dampen cytokine storms and indirectly preserve T cells; checkpoint inhibitors targeting PD-1/PD-L1, CTLA-4, or CD39 may reinvigorate exhausted T cells, but risk immune-related adverse events. IL-7 can restore lymphocyte counts, TCR diversity, and memory formation; low-dose IL-2 may expand Tregs to rebalance inflammation. Adoptive transfer of SARS-CoV-2-specific T cells is being explored but faces logistical and safety challenges. - T cell monitoring: ELISA/ELLA, ELISpot/FluoroSpot, AIM flow cytometry, and qPCR-based assays (qTACT/dqTACT) enable scalable or detailed assessment of T cell immunity; T cell responses can be detected in absence of seroconversion in exposed individuals, underscoring the importance of cellular immunity measurements.

The review consolidates evidence that T cells are pivotal in controlling SARS-CoV-2 infection, limiting disease severity, and providing cross-variant protection due to recognition of conserved viral epitopes. While robust Th1-skewed responses (with balanced IL-10) support viral control and reduced immunopathology, dysregulated activation and cytokine storms can drive tissue injury. Vaccine platforms consistently induce durable Th1-biased CD4+ and CD8+ responses that remain largely effective against VOCs, including Omicron, thereby reducing severe outcomes even when neutralizing antibodies wane. The mixed data on exhaustion markers (e.g., PD-1) indicates functional heterogeneity among T cells during COVID-19, suggesting that simple marker expression is insufficient to define dysfunction. Therapeutic modulation of inflammatory pathways and selective reinvigoration of exhausted T cells represent promising approaches to improve outcomes, though risks of exacerbating inflammation must be managed. Continuous monitoring of T cell responses and epitope conservation is essential as the virus evolves, informing booster strategies and next-generation vaccines prioritizing cellular immunity.

T cell immunity is central to SARS-CoV-2 control, prognosis, and vaccine-mediated protection, with Th1-dominant CD4+ help and cytotoxic CD8+ activity reducing viral loads and severe disease risk. Despite extensive Spike mutations in variants like Omicron, vaccine-elicited T cells largely retain cross-reactivity, supporting durable protection from severe outcomes. Severe COVID-19 is marked by lymphopenia, hyperactivated effector subsets, and features of T cell dysfunction/exhaustion linked to heightened inhibitory checkpoints and cytokine storms. Therapeutic strategies that rebalance inflammatory pathways (e.g., IL-6R, TNF, JAK inhibitors), restore T cell numbers and function (e.g., IL-7, selected checkpoint blockade), or augment virus-specific T cells (e.g., adoptive transfer) may improve clinical trajectories. Future research should clarify mechanisms governing T cell clonal expansion vs. exhaustion, define optimal immunomodulatory regimens to reinvigorate protective T cell responses without precipitating immunopathology, and assess whether variant-specific vaccines are necessary versus optimizing booster strategies to sustain broad, conserved T cell immunity. Ongoing surveillance for T cell epitope escape is critical to maintain population-level protection.

- The review notes limited and sometimes conflicting data on T cell cross-reactivity to VOCs (e.g., loss of recognition for certain mutated epitopes) and on whether PD-1 and other inhibitory markers reflect true functional exhaustion in COVID-19. - Many cited studies have small cohorts, differing severity definitions, sampling biases (blood vs. tissue), and variable timing post-infection/vaccination, limiting generalizability. - Direct causal links between specific T cell phenotypes and clinical outcomes remain to be fully established; the contribution of bystander activation vs. antigen-specific responses in tissues is not fully resolved. - Therapeutic recommendations (e.g., checkpoint inhibitors, cytokine pathway blockers, IL-7/IL-2) are based on preliminary or analogous evidence with potential for immune-related adverse events; optimal dosing, timing, and patient selection require further clinical trials. - As a narrative review, no standardized systematic methodology is described for study selection, which may introduce selection bias.