Weak SARS-CoV-2-Specific Responses of TIGIT-Expressing CD8+ T Cells in People Living with HIV After a Third Dose of a SARS-CoV-2 Inactivated Vaccine
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has had a profound global impact, with over 771 million confirmed cases and 6.96 million deaths reported as of October 2023. Vaccination has been a critical tool in controlling the spread of the virus, reducing severe illness, and improving outcomes. However, the emergence of new variants, such as Omicron, has raised concerns about the durability of vaccine-induced immunity, particularly in immunocompromised populations like people living with HIV (PLWH). This study investigates the role of TIGIT, an inhibitory receptor expressed on T cells, in modulating the immune response to a third dose of an inactivated SARS-CoV-2 vaccine in PLWH compared to healthy controls (HCs).
Background and Rationale
TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains) is a coinhibitory molecule that downregulates T-cell activation and proliferation. It has been implicated in T-cell exhaustion during chronic viral infections, including HIV, and in cancer. TIGIT’s role in the context of SARS-CoV-2 vaccination, particularly in PLWH, remains poorly understood. Given the compromised immune systems of PLWH, understanding how TIGIT expression affects vaccine-induced immunity is crucial for optimizing vaccination strategies in this population.
This study aimed to evaluate the dynamics of TIGIT-expressing T cells in PLWH and HCs after receiving a third dose of an inactivated SARS-CoV-2 vaccine. The research focused on the frequency, activation, subset composition, and SARS-CoV-2-specific immune responses of TIGIT+CD4+ and TIGIT+CD8+ T cells. The findings provide insights into the immune mechanisms underlying vaccine responses in PLWH and highlight potential therapeutic targets to enhance vaccine efficacy.
Study Design and Methods
The study enrolled 45 PLWH on antiretroviral therapy (ART) with undetectable viral loads and 31 HCs. All participants received a third dose of an inactivated SARS-CoV-2 vaccine. Peripheral blood mononuclear cells (PBMCs) were collected at three time points: before the third dose (0W), 4 weeks (4W), and 12 weeks (12W) post-vaccination. The frequency, activation, and subset composition of TIGIT+CD4+ and TIGIT+CD8+ T cells were analyzed using flow cytometry. Additionally, SARS-CoV-2-specific T-cell responses were assessed using an activation-induced marker (AIM) assay, which measured the coexpression of CD137 and CD69 on CD8+ T cells and OX40 and CD137 on CD4+ T cells after stimulation with SARS-CoV-2 spike peptide pools.
Key Findings
TIGIT Expression on T Cells
The study found that the frequency of TIGIT+CD8+ T cells increased significantly in PLWH at 12W post-vaccination but remained stable in HCs. In contrast, the frequency of TIGIT+CD4+ T cells did not change significantly in either group. This suggests that HIV infection may promote the upregulation of TIGIT on CD8+ T cells, potentially impairing their antiviral function.
SARS-CoV-2-Specific T-Cell Responses
SARS-CoV-2-specific TIGIT+CD8+ T-cell responses in PLWH did not increase significantly at any time point, whereas HCs showed a gradual increase, peaking at 12W. Notably, the SARS-CoV-2-specific responses of TIGIT+CD8+ T cells in PLWH were significantly weaker than those of TIGIT–CD8+ T cells at all time points. In contrast, HCs showed no significant difference in the responses of TIGIT+CD8+ and TIGIT–CD8+ T cells at 4W and 12W. This indicates that TIGIT expression may suppress the recall response of CD8+ T cells to vaccine antigens in PLWH.
For CD4+ T cells, SARS-CoV-2-specific TIGIT+CD4+ T-cell responses increased significantly in both PLWH and HCs at 12W. However, there was no significant difference in the responses of TIGIT+CD4+ and TIGIT–CD4+ T cells in HCs, whereas PLWH showed stronger responses in TIGIT+CD4+ T cells at 12W. This suggests that TIGIT expression has a minimal impact on CD4+ T-cell responses in both groups.
T-Cell Activation
The activation of TIGIT+CD8+ T cells, measured by the coexpression of CD38 and HLA-DR, increased significantly in PLWH at 4W and 12W, reaching its peak at 12W. In contrast, HCs showed a decrease in TIGIT+CD8+ T-cell activation at 4W, followed by an increase at 12W. This heightened activation in PLWH may contribute to the increased frequency of TIGIT+CD8+ T cells observed at 12W.
For TIGIT+CD4+ T cells, activation increased significantly in both PLWH and HCs at 12W, with no significant difference between the groups. This indicates that TIGIT expression does not significantly affect the activation of CD4+ T cells in response to vaccination.
T-Cell Subset Composition
The study also examined changes in the subset composition of TIGIT+CD8+ and TIGIT+CD4+ T cells. In PLWH, the proportion of effector memory T cells (TEM) among TIGIT+CD8+ T cells increased at 12W, while the proportions of naïve T cells (TN) and central memory T cells (TCM) decreased. This shift was not observed in HCs, suggesting that HIV infection may alter the memory T-cell response to vaccination.
For TIGIT+CD4+ T cells, the proportion of TCM and TEM subsets increased in PLWH at 12W, while only the TCM subset increased in HCs. This indicates that TIGIT expression may differentially affect the subset composition of CD4+ T cells in PLWH and HCs.
Comparison of TIGIT+ and TIGIT– T Cells
The study compared the activation and SARS-CoV-2-specific responses of TIGIT+ and TIGIT– T cells. In PLWH, the activation of both TIGIT+CD8+ and TIGIT–CD8+ T cells increased at 12W, but the SARS-CoV-2-specific responses of TIGIT+CD8+ T cells were significantly weaker than those of TIGIT–CD8+ T cells. In contrast, HCs showed no significant difference in the activation or responses of TIGIT+CD8+ and TIGIT–CD8+ T cells at 4W and 12W.
For CD4+ T cells, the activation of both TIGIT+ and TIGIT– subsets increased in PLWH and HCs at 12W. However, PLWH showed stronger SARS-CoV-2-specific responses in TIGIT+CD4+ T cells at 12W, whereas HCs showed no significant difference between the subsets.
Discussion
The findings of this study highlight the role of TIGIT in modulating the immune response to SARS-CoV-2 vaccination in PLWH. The increased frequency and activation of TIGIT+CD8+ T cells in PLWH, coupled with their weaker SARS-CoV-2-specific responses, suggest that TIGIT expression may impair the antiviral function of CD8+ T cells in this population. This is consistent with previous studies showing that TIGIT contributes to T-cell exhaustion during chronic viral infections.
The study also underscores the importance of TIGIT–CD8+ T cells in mediating the immune response to vaccination in PLWH. The robust activation and SARS-CoV-2-specific responses of TIGIT–CD8+ T cells suggest that these cells play a critical role in combating SARS-CoV-2 infection in PLWH. This finding has important implications for the development of therapeutic strategies aimed at enhancing the efficacy of vaccines in immunocompromised populations.
The differential effects of TIGIT expression on CD4+ and CD8+ T cells observed in this study suggest that TIGIT may have distinct roles in regulating the immune responses of these cell types. While TIGIT expression had a minimal impact on CD4+ T-cell responses, it significantly impaired the recall response of CD8+ T cells to vaccine antigens in PLWH. This highlights the need for further research to elucidate the mechanisms underlying these differences and to explore the potential of TIGIT blockade as a therapeutic intervention.
Limitations
The study has several limitations. First, it focused on PLWH on ART with well-controlled HIV infection, limiting the generalizability of the findings to individuals with poor immune statuses, such as low CD4+ T-cell counts or high viral loads. Second, the study did not investigate the impact of sex on the immune response to vaccination, which should be addressed in future research with larger sample sizes.
Conclusion
This study provides valuable insights into the role of TIGIT in modulating the immune response to SARS-CoV-2 vaccination in PLWH. The findings suggest that TIGIT expression hinders the specific T-cell immune response to vaccine antigens, particularly in CD8+ T cells, and may weaken resistance to SARS-CoV-2 infection in PLWH. These results have important implications for the development of vaccination strategies and therapeutic interventions aimed at enhancing the immune response in immunocompromised populations. Further research is needed to explore the potential of TIGIT blockade as a means of improving vaccine efficacy in PLWH and other high-risk groups.
doi.org/10.1097/CM9.0000000000002926
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