Understanding the Basics of Memory T Cells

When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor (TCR) on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen.

To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. 

Some of these short-lived effector cells—according to the generally accepted theory—turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter.  

Now a new research has found that memory T cells may have been formed earlier than previously thought.^[17]

"Understanding the basis of effective long-term immune memory may help scientists develop better vaccines, understand differences among diseases and diagnose the quality of an individual person's immune responses," says Marc Hellerstein, professor of nutritional science and toxicology.^[13]

 

Immune Memory

Immune memory (or immunological memory), from either primary infection or immunization, is the source of protective immunity from a subsequent infection.^[3-5] Thus, COVID-19 vaccine development is closely tied to the topic of immunological memory.^[6,7]

A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including:^[2]

• B cells (aka B lymphocytes)
• CD8+ T cells (aka killer T-cells or cytotoxic T cells)
• CD4+ T cells (i.e., T helper cells)

as these different cell types may have immune memory kinetics relatively independent of each other. In this article, we will discuss memory T cell in the context of SARS-CoV-2 infection.

Studies of acute and convalescent COVID-19 patients have observed that T cell responses are associated with lessened disease, suggesting that SARS-CoV-2-specific CD4+ T cell and CD8+ T cell responses may be important for control and resolution of primary SARS-CoV-2 infection.

Pre-Existing Immunity

SARS-CoV-2 is a novel human pathogen. SARS-CoV-2 is a member of the coronavirus family that includes human coronaviruses (HCoVs) HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63—betacoronaviruses and alphacoronaviruses that cause common colds.^[18] 

SARS-CoV-2 is relatively distantly related to those four endemic HCoVs, with <10% aa identity in the Spike RBD. As a result, 

• Cross-reactive circulating anti-Spike cross-neutralizing antibodies 
• Are rare^[2-6]
• Cross-reactive Spike memory B cells 
• Are rare
• Cross-reactive T cell memory^[7-9]
• Is reported in ∼28%–50% of people
• In a new study,^[24] it concludes that prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination may elicit cross-reactive T cells that mitigate COVID-19.
• The majority of the SARS-CoV-2 cross-reactive T cells are CD4+ T cells^[9]
• These have been demonstrated to be memory T cells and many are memory T cells to common cold coronaviruses with conserved epitopes^[10]
• Cross-reactive CD8+ T cells are observed less frequently.  But may still be biologically relevant.^[11]

The relatively slow course of severe COVID-19 in humans (median 19 days post-symptom onset (PSO) for fatal cases^[13]) suggests that protective immunity against symptomatic or severe 2° COVID-19 may very well involve memory compartments such as circulating memory T cells and memory B cells (which can take several days to reactivate and generate recall T cell responses and/or anamnestic antibody responses).^[14-16]

T Cell Memory

In the study of Shane Crotty et al,^[12] they assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a cross-sectional study of 185 recovered COVID-19 cases, extending out to greater than six months post-infection. 

Here are the summary of their results on SARS-CoV-2-specific memory of:

• B cells
• Overall, based on the observations, development of B cell memory to SARS-CoV-2 appeared to be robust and likely long-lasting
• Read [21] for more details.
• CD8+ T cells 
• The memory CD8+ T cell half-lives (or t_1/2) observed herein were comparable to the 123d t_1/2 observed for memory CD8+ T cells within 1-2 years after yellow fever immunization.^[10]
• Overall, the decay of circulating SARS-CoV-2-specific CD8+ T cell is consistent with what has been reported for another acute virus.
• CD4+ T cells
• Circulating SARS-CoV-2 memory CD4+ T cell responses were quite robust
• 94% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at 1 month PSO
• 89% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at ≥ 6 months PSO
• In individuals who recovered from mild COVID-19, CD4+ T cells gained a typical memory phenotype with high levels of expression of IL-7Rα.^[23]

Their findings have implications for immunity against 2° COVID-19, and thus the potential future course of the pandemic.^[19,20]

Compared with their naïve precursors, memory T cells are more abundant, have a lower threshold for activation, and more rapidly reactivate effector functions following antigen encounter. They are also maintained in barrier tissues to rapidly respond to reinfection. Thus, a major goal of vaccines is the induction of strong and durable T and B cell memory.

 

References

1. Adaptive immunity to SARS-CoV-2 and COVID-19
2. Amanat et al., 2020 A serological assay to detect SARS-CoV-2 seroconversion in humans
3. Okba et al., 2020 Severe acute respiratory syndrome coronavirus 2− specific antibody responses in coronavirus disease patients
4. Suthar et al., 2020 Rapid generation of neutralizing antibody responses in COVID-19 patients
5. Tan et al., 2020b A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction
6. Wec et al., 2020 Broad neutralization of SARS-related viruses by human monoclonal antibodies
7. Le Bert et al., 2020 SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls
8. Braun et al., 2020 SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
9. Grifoni et al., 2020 Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals
10. Mateus et al., 2020 Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans
11. Schulien et al., 2020 Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells
12. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection
13. F. Zhou, T. Yu, R. Du, G. Fan, Y. Liu, Z. Liu, J. Xiang, Y. Wang, B. Song, X. Gu, L. Guan, Y. Wei, H. Li, X. Wu, J. Xu, S. Tu, Y. Zhang, H. Chen, B. Cao, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 395, 1054–1062 (2020).
14. N. Baumgarth, J. Nikolich-Žugich, F. E.-H. Lee, D. Bhattacharya, Antibody Responses to SARS-CoV-2: Let’s Stick to Known Knowns. J Immunol, ji2000839 (2020).
15. A. Sariol, S. Perlman, Lessons for COVID-19 immunity from other coronavirus infections. Immunity. 53, 248–263 (2020).
16. D. M. Altmann, R. J. Boyton, SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Sci Immunol. 5, eabd6160 (2020).
17. How the immune system remembers viruses: Memory T cells are formed earlier than previously thought
18. Human Coronavirus: Host-Pathogen Interaction
19. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 368, 860–868 (2020).
20. C. M. Saad-Roy, C. E. Wagner, R. E. Baker, S. E. Morris, J. Farrar, A. L. Graham, S. A. Levin, M. J. Mina, C. J. E. Metcalf, B. T. Grenfell, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science, eabd7343 (2020).
21. Understanding the Basics of Memory B Cells—The Antibody Factory
22. Coronavirus Deranges the Immune System in Complex and Deadly Ways
23. Neidleman, J. et al. SARS-CoV-2-specific T cells exhibit unique features characterized by robust helper function, lack of terminal differentiation, and high proliferative potential.
24. Protective heterologous T cell immunity in COVID-19 induced by the trivalent MMR and Tdap vaccine antigens
25. Antigenic drift: Understanding COVID-19 (good)