A new study reports that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces protective tissue memory that includes both humoral and cellular elements to protect specific tissue sites, such as the lung and lung-associated lymph nodes, against infection.
Study: SARS-CoV-2 Infection Generates Tissue-Localized Immunological Memory In Humans. Image Credit: Yurchanka Siarhei / Shutterstock.com
Background
The coronavirus disease 2019 (COVID-19) pandemic has brought about immense harm to human health, social, and psychological well-being, as well as economic activity. Thus, herd immunity is necessary in order to bring this pandemic to an end.
The ability to achieve herd immunity largely depends on a phenomenon called immune memory. SARS-CoV-2 infects the respiratory tract, which subsequently induces adaptive immune responses that includes T- and B-cells that specifically recognize the virus and clear it from the infected cells in the lungs and other infected tissues. Simultaneously, this response blocks the spread of the virus through T-cell effector functions and antibodies.
Both antibodies and T-cells specific to SARS-CoV-2 can be found in peripheral blood for up to a year following infection. Neutralizing antibody titers elicited by COVID-19 vaccines are directly associated with protective immunity. However, several SARS-CoV-2 variants have and continue to emerge, many of which threaten to escape protective neutralizing antibodies and cause breakthrough infections.
Memory immune cells are therefore key to a broadly protective immune response that can counter new strains that have yet to emerge. However, most research has been confined to cells from the blood, while adaptive immunity is active within tissues, sites of infection, and lymphoid organs.
Virus-specific CD4 and CD8 T-cells consist of both circulating and non-circulating subsets. The latter comprises tissue-resident memory cells (TRM), which are associated with the optimal protection against respiratory infection in the lungs and lung-associated lymph nodes.
Most T-cells in adults are memory cells, including TRM in mucosal and epithelial sites, as well as in exocrine sites. At lymphoid sites, however, circulating T effector cells (TEM) and T central memory cells (TCM) are also present with TRM. Tissue memory cells have a different gene expression signature as compared to those present within the blood.
Memory B-cells are generated in the lymph nodes and spleen when virus-specific follicular helper T-cells (TFH) trigger the differentiation and maturation of B-cells. These then persist in tissues with specific phenotypes at different locations, conferring protection on the tissue. Memory B-cells are dominant in human lymphoid and mucosa, but naïve cells in the blood.
The airways in patients with severe COVID-19 patients have been found to contain activated TEM and TRM. Comparatively, blood samples from these patients consist of B-cells specific to the viral spike (S), receptor-binding domain (RBD), and nucleocapsid (N) antigens.
In the current study, the researchers explored specific memory T- and B-cells in lymphoid and mucosal tissue from organ donors with a history of prior SARS-CoV-2 infection and with antibodies in their serum.
Study findings
The results of the current study show spike-specific CD4 T-cells to be predominant at all the sites, including the bone marrow, spleen, lung, lung-associated lymph nodes, and gut-associated lymphoid tissue. CD4 cells specific to other viral epitopes were found in the bone marrow, as well as lung- and gut-associated lymphoid tissue.
Overall, virus-specific CD4 T-cell responses correlated with S protein-specific responses. CD8 T-cells were found at lower levels with greater differences between donors. Both types of cells were most common in the lung tissue and lung-associated lymph nodes.
While 75% of virus-specific CD4 T-cells in the blood and lungs were TEMs, 80% in the lymphoid sites were TEM or TCM. With CD8 T-cells, over half at any site were TEMs or terminally differentiated effector T-cells (TEMRA). At certain sites including the lungs, bone marrow, and spleen, TEMRA was dominant.
Memory T-cells specific to SARS-CoV-2 were thus found over multiple sites, with TRMs persisting mostly in the lungs. The functional responses to the virus differed across sites, as well as individual patients.
For instance, functional responses in the lymph nodes included inflammatory cytokines and cytolytic mediators, such as interferon γ (IFN-γ), tumor-necrosis factor α (TNF-α), granzyme B, perforin, granulocyte-macrophage colony-stimulating factor (GM-CSF). They also included type 2 and type 3 cytokines, mostly at higher concentrations.
In the lungs, blood, and bone marrow, proinflammatory cytokines including TNF-α, perforin, granzyme B, and regulatory molecules interleukin 10 (IL-10) characterize the response. The lung response also includes other inflammatory molecules, with higher levels of IL-6 and Il-15. Thus, memory T-cells at different sites have characteristic functional responses optimal for the site, helping to provide well-rounded protection.
B-cells in the tissues mostly expressed virus-specific immunoglobulin G (IgG). Over 40% expressed IgM in the bone marrow and spleen, as compared with few in the lymph nodes. The highest frequency was in the lung and lung-associated lymph nodes.
The current study showed that SARS-CoV-2 induces the formation of tissue-resident B-cells (BRM) specific for human antigens in both lungs and lymph nodes that are different from those in the blood. Most of these cells were positive for CD69.
Within the lymphoid organs, germinal centers (GCs) offer places where activated B-cells are recognized by TFH in order to undergo antibody maturation of pathogens. SARS-CoV-2 induces specific GC responses that persist in lung-associated lymph nodes after the infection clears. Long-term GCs are also induced in human gut-associated lymph nodes.
Specific memory B-cells in the lung-associated lymph nodes were inversely correlated with spike-specific CD4 T-cells in the lungs. Similarly, TFH cells in the lung-associated lymph nodes were correlated with lung memory B-cells, as well as CD4 T-cells with GC B-cells in the lung-associated lymph nodes. Thus, humoral and cellular immunity act in a coordinated manner in the lungs and lung-associated lymph nodes.
Implications
The discovery of TRM and BRM in abundance in the lungs, along with virus-specific GC B-cells and TFH cells in lung-associated lymph nodes, indicates that immune memory to SARS-CoV-2 is characterized by a synchronized and continuing match of humoral and cellular immunity within tissues.
The lungs and associated lymph nodes are key sites for immune memory induction following SARS-CoV-2 infection, as these areas were found to contain virus-specific memory T- and B-cells. The low frequency at which these cells are found in the spleen indicates that the infection is limited to mucosal entry sites. Tissue-resident memory T and B cells in the lung are likely to be required to protect these specific sites and may experience a boost in site-specific immune responses following vaccination.
The study also demonstrates tissue-specific functional responses of T-cells directed against the virus, with a broadly distributed virus-specific memory B-cell response. The lymph nodes show long-term GC responses after the infection clears across age groups from 10-74 years.
This is the first time that such centers have been shown to provide long-term protection against SARS-CoV-2 infection, thus ensuring that antibody maturation occurs and keeping antibody titers elevated. Even older people responded with robust memory immune responses.
“Together, these findings suggest that dynamic coordination of adaptive immune responses across the body is a feature of antiviral immunity to SARS-CoV-2.”
This could lead to the development of methods to monitor immune memory and strengthen immune responses at the sites of infection.
“Our study suggests that to improve protection against the virus, vaccines should target the memory immune cells within the lung and its associated lymph nodes, which can be accomplished with nasal sprays of disabled viruses. We’ve found previously in mice with influenza that memory T cells in the lung are needed for optimal protection against respiratory infections, and this study strongly suggests that the same could be true in people.”
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