Regulation of T cell responses by ∆42PD1 or mitochondria during viral infections

Abstract

T lymphocyte (also called T cell), essential for host adaptive immunity, accounts for the majority of peripheral lymphocyte. It consists of around 95% αβ- and 5% γδ-T cell populations based on the expression of T cell receptors (TCRs). αβ-T cell is the main T cell population, which serves either as CD4+ T helper for inducing both antibody and cytotoxic T lymphocyte (CTL) responses or as CD8+ CTL for eliminating virus-infected cells. Upon viral infections, naïve αβ-T cells get priming into various functionality through TCR activation. Besides TCR activation, αβ-T cell responses can also be profoundly regulated by toll-like receptors (TLRs), cytokines and metabolic activities. Similarly, these regulatory factors may regulate γδ-T cells for different functions such as antigen-presentation and natural killer. I, therefore, hypothesized that different types of viral infection might engage distinct mechanisms to regulate T cell responses. During my PhD study, I sought to determine how the external stimulatory ∆42PD1/TLR4 signal through γδ-T cells and the internal metabolic mitochondria affected αβ-T cell responses in the context of different viral infections. Based on our previous study that ∆42PD1-expressing Vδ2 T cells could trigger TLR4 downstream signaling, I hypothesized that ∆42PD1-expressing Vδ2 T cells could be involved in stimulating TLR4-expressing αβ-T cells. During the study, I found that ∆42PD1/TLR4 was engaged in CD4+ T cell stimulation by IL-12/IL-15-activated Vδ2 T cells. Treatment of IL-12/IL-15 promoted the development of the antigen-presentation potential of Vδ2 T cells through high co-expression of ∆42PD1 and HLA-DR. Transitional memory TLR4+ CD4+ T cells were responsive to IL-12/IL-15-activated ∆42PD1-expressing Vδ2 T cells in antigen-bearing autologous co-culture systems. My findings demonstrated the importance of ∆42PD1/TLR4 in regulating CD4+ T cell responses. This innovative finding might implicate the possible involvement of ∆42PD1/TLR4 signaling in patients with acquired immunodeficiency diseases, in whom both an elevated proportion of ∆42PD1-expressing Vδ2 T cells and an increased percentage of TLR4+ CD4+ T cells were reported. For intracellular T cell regulation, mitochondria activity is essential in regulating αβ-T cell fate. Given that lymphocytopenia and functional exhaustion of αβ-T cells were reported in acute patients with the coronavirus disease 2019 (COVID-19), I hypothesized that mitochondria activity might play a role during SARS-CoV-2 infection. By investigating acute COVID-19 patient samples using flow cytometry, I found that the increased mitochondrial dysfunction (MD) in T cells was related to T cell hyperactivation and lymphocytopenia during acute infection. Furthermore, this MD phenotype was found to be associated with profoundly reduced TEM cell functionality, especially poor antigen-specific CD4+ TEM cell responses. On the one hand, distinguishable from MD-associated αβ-T cell functional exhaustion previously found in chronic viral infection, my findings provide new evidence that similar association also occurred in acute SARS-CoV-2 infection. On the other hand, in mild COVID-19 patients with higher MD around 11-15 days post symptom onset, MD-associated TEM cell functional exhaustion might play a suppressive role in immunopathogenesis. My research findings, therefore, expand current knowledge on distinct TLR4-activated or mitochondria-related mechanisms involved in regulating T cell responses in the context of two infectious diseases, respectively.