The Role of Lymphocytes In Antiviral Responses To SARS-Cov-2

Viral entry and destruction depend on the recognition of special protein fragments to elicit an immune response. Lymphocytes are specialized to recognize antigens (any molecule or partial molecule that triggers an immune response) and initiate a response.

COVID-19 Structure by Esra Almaeeni,
Youth STEM Matters Artist

B and T lymphocytes have receptors known as B cell receptors (BCR) and T cell receptors (TCR) respectively. These receptors are specific for a particular antigen (molecule presented on the membrane of a foreign organism). In fact, the coronavirus has specific proteins on its outer coat. The BCR has a complementary shape specific for these membrane proteins, and the two bind in a lock and key fashion. Upon viral binding to the coronavirus, the B cell becomes activated. An activated B cell is referred to as a ‘plasma cell’, which is capable of producing immunoglobulins, otherwise known as antibodies. Different types of immunoglobulins (Ig) exist. IgM and IgG antibodies to SARS-CoV-2 can be detected a few days after contracting the virus [1]. The antibodies bind onto the antigen on the coronavirus and ‘mark’ it for destruction by other cells [2]. Specifically, antibodies cause agglutination, or the clumping together of coronavirus molecules, making them easier to destroy by phagocytosis. They can also make the virus ‘more appealing’ (opsonization) to phagocytes, such as neutrophils, which engulf them through a series of intracellular processes that eventually destroy the coronavirus. 

There are two types of T lymphocytes that exist: CD4+, or helper cells, and CD8+, or cytotoxic cells. They have receptors that bind onto major histocompatibility complex (MHC) molecules that have certain protein molecules [3]. Binding of T lymphocytes is much like that of B lymphocytes, except T lymphocytes do not become activated to produce antibodies. After binding, they undergo clonal selection to replicate and form more T lymphocytes with the TCR specific for coronavirus and then attack. The helper cells assist in the development of cytotoxic cells, which have the ability to kill the virus [4]. Cytotoxic cells kill the virus by inducing apoptosis (programmed cell death) of infected cells.

Eventually as viral load increases, the number of available lymphocytes assisting in eliminating the coronavirus decreases, thus lowering the person’s ability to fight the coronavirus. A study investigating this showed that “the total number of NK [natural killer] and CD8+ T cells was decreased markedly in patients with SARS-CoV-2 infection” [5]. This is especially important in understanding why immunocompromised individuals are at a much higher risk of death if they contract coronavirus. The deficiency of necessary immune cells is exacerbated upon infection to a point where the immune system is completely incapable of fighting the coronavirus, and ultimately the patient dies. Lymphopenia, simply defined as inadequate numbers of lymphocytes, is a major determinant in the severity of COVID infection. Research shows that “the presence of lymphopenia was associated with nearly threefold increased risk of severe COVID-19” [6].

It has been widely accepted that individuals susceptible to contracting and suffering severe coronavirus symptoms include the elderly. An interesting investigation, however, found a link between lymphocytes and age-related immunocompetence. It concluded that young people are more susceptible to experiencing severe coronavirus symptoms. The research suggested that “the association between lymphopenia and severe COVID-19 was stronger in younger patients” [7]. Hypothetically speaking, the immune system becomes “non-reactive” with age, such that the lymphocyte count stabilizes. Consequently, a younger immune system is more reactive and at risk of fluctuations in lymphocyte counts [7]. Such studies offer plausible explanations for why people at any age are susceptible, especially once a correlation with lymphocytes is made.  Another study has proven that T lymphocyte response can vary depending on the severity of COVID [8], which suggests and confirms that people respond to COVID slightly differently, a phenomenon that aids in vaccine research.

It is evident that the role of lymphocytes is key in coronavirus elimination from the body, and anything acting to decrease lymphocyte count has detrimental, often fatal, effects on the body. An appreciation of how lymphocytes work, and why their depletion in SARS-CoV-2 is important can enable a better understanding of this pandemic and how to combat it to develop.

References

[1] European Centre for Disease Prevention and Control, "Immune responses and immunity to SARS-CoV-2," European Centre for Disease Prevention and Control, 11 June 2020. [Online]. Available: https://www.ecdc.europa.eu/en/covid-19/latest-evidence/immune-responses. [Accessed 7 July 2020].

[2] H. D. E. Lopera and R. L. E. L. E. Cano, "Introduction to T and B lymphocytes," in Autoimmunity: From Bench to Bedside, Bogota, El Rosario University Press, 2013, pp. 77-97.

[3] K. E. Barret, S. Boitanno, S. M. Barman and H. L. Brooks, Ganong’s Review of Medical Physiology, 25th ed., New York: McGraw-Hill Education, 2016.

[4] N. B. Marshall and S. L. Swain, "Cytotoxic CD4 T Cells in Antiviral Immunity," Journal of Biomedicine and Biotechnology, vol. 2011, p. 1, 2011.

[5] Z. Tian, Y. Gao, Y. Xu, M. Zheng, S. Liu, G. Song, G. et al., "Functional exhaustion of antiviral lymphocytes in COVID-19 patients," Cellular and Molecular Immunology, no. 17, p. 543, 2020.

[6] L. Yang, Z. Weng, Y. Deng, J. Huang, Y. Wu, R. Kumar, et al., "Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis," International Journal of Infectious Diseases, vol. 96, p. 135, 2020.

[7] I. Huang and R. Pranata, "Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis," Journal of Intensive Care, vol. 8, no. 36, 2020.

[8] D. Weiskop, K. S. Shmitz, A. Grifoni and M. P. Raadsen, "Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome," Science Immunology, vol. 5, no. 48, p. 1, 2020.