Accelerated T-cell exhaustion: its pathogenesis and potentially severe outcomes

Several cancers and intracellular pathogens subvert immune defenses using proteins and short non-coding ribonucleic acids (RNAs) [1]. Non-coding RNAs can bind to host cell signal transducer and activator of transcription (STAT) transcription factors and messenger RNAs to disrupt gene expression of interferon-stimulated genes (ISG) and messenger RNA processing, enabling pathogens to evade immune cells including natural killer cells (NK-cells), thymic cells (T-cells) and bone marrow cells (B-cells) [1]. Furthermore, ISG disruption could disrupt ISG cellular defenses targeting other pathogens within the host cell.

T-cell exhaustion inhibits T-cell functions for CD4⁺ and/or CD8⁺ T-cells, and results from chronic infections producing continuous antigens [2, 3]. T-cell exhaustion comprises T-cell metabolic exhaustion and mitochondrial dysfunctions, reduced proliferation and effector functions, and potentially diminished T-cell numbers [3].

T-cell exhaustion inhibits CD4⁺ and CD8⁺ T-cell reactions to pathogen infections [3]. T-cell inhibitory receptors participate in T-cell exhaustion, including the programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 protein (LAG-3) [2, 3].

However, inhibitory receptors are also expressed during T-cell differentiation or activation, and their presence during active infections doesn’t necessarily indicate T-cell exhaustion [4]. Furthermore, during acute infections, certain cytokines can increase T-cell expression of inhibitory receptors within 24 h, and substantially increase expression within 48–72 h [4].

How can T-cell exhaustion in antigen-specific T-cells impair T-cells targeting other pathogens? A chronic first pathogen infection can accelerate T-cell exhaustion for a second pathogen using cytokines causing T-cell inhibitory receptor (e.g., PD-1) expressions, and by inducing infected cells to express inhibitory ligands (e.g., PD-L1) for those inhibitory receptors [2]. A second pathogen infection can utilize the infected cell's expressed inhibitory ligands to accelerate exhaustion of T-cells targeting the second pathogen. This could potentially enable the second pathogen to overcome the host's immune defenses [2]. This could be dangerous in novel infections where antibodies (produced from B-cells by CD4⁺ T-cell assistance) are numerically insufficient and/or inadequate in affinity selection/maturation from somatic hypermutation to suppress the second pathogen [5]. Mortality could occur, where the second pathogen infection induces accelerated T-cell exhaustion and the second pathogen overwhelms the host's immune system.

In murine T-cell exhaustion, if antigen exposure from lymphocytic choriomeningitis virus (LCMV) is continuous, T-cell exhaustion first appears at about two weeks post-infection and an irreversible complete T-cell exhaustion phenotype is seen approximately four weeks post-infection [3]. If it is plausibly assumed that other viruses in mice or humans have approximately the same timing regarding conventional T-cell exhaustion, and infection mortality is approximately contemporaneous with completely developed T-cell exhaustion, COVID-19 pandemic mortality timing statistics might discern between conventional and accelerated T-cell exhaustion fatalities [6].

CD8⁺ and CD4⁺ T-cell exhaustion participates in COVID-19 mortality [6]. Exhaustion can also affect follicular helper CD4⁺ T-cells, in lymph node and spleen germinal centers, essential for antibody affinity maturation, isotype switching, generation of memory B-cells, and B-cell differentiation into immunoglobulin (antibody) secreting plasma cells [7]. Accelerated T-cell exhaustion could be lethal in first-time infections by the second pathogen, if germinal center follicular helper CD4⁺ T-cells are inhibited, causing immunoglobulin/antibody B-cell expressions to lack optimal immunoglobulin/antibody isotype switching and impair immunoglobulin/antibody improvements by somatic hypermutation and affinity selection/maturation to better target the second pathogen [5]. Patients experiencing severe COVID-19 express higher proportions of less-developed IgM immunoglobulins, compared to control or mild COVID-19 patient immunoglobulin expressions [7]. This suggests follicular helper CD4⁺ T-cell exhaustion contributes to severe COVID-19 cases and mortalities [5, 7].

If conventional or accelerated T-cell exhaustion cause COVID-19 mortalities, the timings for conventional T-cell exhaustion, accelerated T-cell exhaustion and patient mortality are relevant. Statistical analysis of 8873 COVID-19 patient mortality cases calculated a median time from COVID-19 symptoms/diagnosis to death (16.33 days for male patients and 17.67 days for female patients), including cases primarily of Alpha through Delta variants of SARS-CoV-2 [8].

A significant difference in the time required for complete T-cell exhaustion induced by the viral pathogens SARS-CoV-2 or LCMV is possible. However, T-cell exhaustion induced by SARS-CoV-2 or other viral pathogens should have approximately equal timing, since the timing depends on the T-cells and host cells, including the times required for T-cell inhibitory receptor expression and for infected host cell expressions of inhibitory ligands. In murine LCMV infections, T-cell exhaustion characteristics first appear ~ 15 days post-infection and irreversible complete T-cell exhaustion characteristics appear at ~ 30 days [9].

Comparing the times from symptoms/diagnosis of COVID-19 to death is possible, using an adjustment factor for the delay from infection to symptoms/diagnosis. One study determined the incubation period for COVID-19, defined as the time from exposure (infection) to the appearance of COVID-19 symptoms, for the SARS-CoV-2 Alpha, Beta, Delta, and Omicron variants [10]. The mean incubation period of COVID-19 ranged from five days for the Alpha variant to 3.42 days for the Omicron variant [10]. Subtracting five days as a conservative delay after exposure for any variant of SARS-CoV-2 to produce COVID-19 symptoms/diagnosis suggests that conventional complete T-cell exhaustion appears ~ 25 days after symptoms/diagnosis of COVID-19.

Although patient co-infections and comorbidities could cause several COVID-19 mortalities and cause statistical shifts, the median times (~ 16 to ~ 18 days) from COVID-19 symptoms/diagnosis to death remain puzzling, because these times are less than the expected ~ 25 days for conventional complete T-cell exhaustion, plausibly contemporaneous with death.

Accelerated T-cell exhaustion is one plausible explanation for the median times of ~ 16 to ~ 18 days for fatalities due to the SARS-CoV-2 Alpha through Delta variants [8], instead of the expected ~ 25 days. Thus, accelerated T-cell exhaustion could be more plausible than conventional T-cell exhaustion for ~ 50% of COVID-19 patient fatalities.

In conclusion, intracellular pathogen interactions could enable accelerated T-cell exhaustion for a second pathogen. Acceleration of T-cell exhaustion is facilitated when the first and second pathogens infect the same cells, allowing reuse of the already expressed inhibitory ligands of the infected cells. The total time for T-cell exhaustion may be the shorter time required for T-cells targeting the second pathogen to express inhibitory receptors. Accelerated T-cell exhaustion, and possibly contributing B-cell dysfunctions, could explain significant mortality rates for some epidemics, including COVID-19, when host immune system defenses are overwhelmed.

Author contributions

No other author contributed to this paper.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Declarations

Conflict of interest

The author has no relevant financial or non-financial interests to disclose.

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No ethical approval was required as this is a review article with no original research data.