There are several proposed mechanisms for lymphocyte depletion and exhaustion:

- Direct entry of SARS-CoV-2 into T cells and macrophages due to interactions between S proteins on the virus and ACE2 receptors on lymphocytes (especially T cells)
- Increased inflammatory cytokines may cause T cell depletion and exhaustion
- Destruction of lymphatic organs, inducing lymphopenia
- Increased levels of lactic acid, which may inhibit lymphocyte proliferation  

Smith College

Studies have shown that T cells are very active in response to SARS-CoV-2. As a result, patients with COVID-19 can show evidence of T cell exhaustion. In severe cases, apoptosis in CD8+ T cells is unusually frequent, also reducing functional diversity. 

Lymphocyte Activation and Dysfunction 


Decreased levels of lymphocytes, or lymphopenia, is a key indicator of severe COVID-19. While T cell and NK cell levels have been found to be significantly reduced, B cell count remains within a normal range. Because lymphopenia is so distinctive of COVID-19, it has been proposed as a tool to measure both the severity of COVID-19 and the prognosis of the patient. 

Lymphopenia 

Yang, Li, et al. “COVID-19: Immunopathogenesis and Immunotherapeutics.” Signal Transduction and Targeted Therapy, vol. 5, no. 1, 2020, doi:10.1038/s41392-020-00243-2.

https://www.nature.com/articles/s41392-020-00243-2

COVID-19: Immunopathogenesis and Immunotherapeutics

Potential Mechanisms of SARS-CoV-2-induced Depletion and Exhaustion of Lymphocytes 

Lymphocytes (i.e WBC's) can be divided into T cells, B cells and Natural Killer cells. The role of T cells is to activate the immune system, directly kill the antigen containing cell and produce cytokines to alert other immune cells in the body. T cells can further be divided into three subsets based on their functions. The three subsets are Cytotoxic T cells (CD8+), Helper T cells (CD4+) and Regulatory T cells. The function of Cytotoxic T cells is to kill the target cell by injecting cytotoxic granules into the infected cell. Helper T cells activate other phagocytic cells by releasing cytokines. Regulatory T cells down regulate the immune system. 

Role of T- cells in Immune functions

Studies have shown that fungal infections are significantly higher in patients with severe COVID-19 and low lymphocyte levels than in patients with high lymphocyte levels, indicating that patients with lymphopenia may be more susceptible to microbial infections. Additionally, microbial infection has been shown to increase disease progression and severity. 

Clinical Implications of SARS-CoV-2-induced Lymphopenia: Microbial Infection 

Cytokine and SARS-CoV-2 entry into the median eminence of the hypothalamus could activate the autonomic nervous system and the release of adrenal catecholamines and steroids. These effectors could act on the bone marrow to release immunosuppression neutrophils and myeloid cells, leading to immunosuppression and lymphopenia. 

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