The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented global crisis creating huge uncertainty – for almost every part of life. Governments are rapidly designing and implementing emergency response measures to deal with the unfolding crisis. At the same time, scientists from around the world are working on developing vaccines for COVID-19 disease. Some of the research focus is now shifting to understanding how the disease is caused.
Now, a new study published in the journal Signal Transduction and Targeted Therapy in August 2020 shows that while humoral and T-cell immune responses are more robust in severe infection, the disease activates memory T cells as part of the adaptive immune system in COVID-19 patients irrespective of disease severity.
Adaptive Immunity in Pathogenic CoV infection
Earlier studies have shown that in MERS, SARS, and influenza, the adaptive immune cells, and especially the lymphocytes, are vital in defending the body against the virus. Many studies have confirmed this in COVID-19, with both antibody and cellular defenses being recruited to the fight. The current study thus aimed to examine the immune system in convalescent COVID-19 patients to obtain a clearer understanding of how the recovery occurred, and how adaptive immunity is related to disease severity.
The study focused on peripheral T cells and B cells from five and four convalescents who had been severely and moderately/mildly ill with COVID-19. Disease severity was classified based on the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment.
Activating T cells and B cells in immune system 3d illustration. Image Credit: Sciencepics / Shutterstock
The researchers then looked at the usage of V(D)J genes among the subjects, since these decide the different patterns and preferences for B and T cells receptors in these patients. They found that healthy people, individuals with mild COVID-19, and those with severe COVID-19, all had distinct clonotypes. There were many genes from the IGHV family. One of these B cell clones was rare in IgG memory B cells from healthy individuals but was overrepresented in one patient who had recovered from severe illness. The most commonly represented VJ segments in this gene family of B cell receptor clones were also specific for the virus.
Comparing severe with mild disease, they found that the genes IGHV3-23, IGHV3-48, IGHV1-2, and IGHV4-34 were dominant in the former. Some genes were also found to be highly expressed in other viral infections, including influenza and cytomegalovirus.
Based on common genes in the IGHV and IGHJ group, they found public clusters of antibody sequences in the patients but not in the controls, which they attributed to the presence of COVID-19. Altogether, there were 19 shared IgG, and 25 shared IgA antibodies among the COVID-19 patients. The further study supports the idea that there is a pattern of humoral and cellular adaptive immunity specific to COVID-19 in mild and severe form.
Changes in Cell Composition and Function
The researchers found no marked changes in the T cell composition in recovered COVID-19 patients, but there were a subset of CD8 T effector memory (TEM) cells in all patients compared to the controls. This may indicate that these cells proliferate in this infection. A subset called CD8+ terminal effector (TTE) cells is found at elevated levels, especially with severe infection. These are cytotoxic cells for the most part. Both the CD4 and CD8 TTE, as well as the CD8 TEM, are clonally expanded in patients.
The researchers comment, “These clonally expanded T cells may represent SARS-CoV-2-specific CD8+ or CD4+ T cells. The transcriptional homogeneity in the COVID-19 patients [may further support this] idea.”
Mucosal associated invariant T (MAIT) cells are reduced markedly in both mild and severe patients, which perhaps reflects an incomplete recovery of the immune system in these patients in the early phase. This has been observed in other viral conditions as well. The presence of plasmablasts in severely ill recovered patients further indicates that these patients respond with a more robust antibody response vs. mild illness. The clonal expansion of BCR and B-cell activation supports this conclusion.
Differential Gene Expression
Differentially expressed genes (DEG) shows that some immune- and inflammation-related pathways are expressed at an obviously different level in the CD4 T cells, CD8 T cells, and AEBCs in all patients vs. healthy controls. These include pathways of cytokine production and leukocyte cell-cell adhesion, mostly in the CD4 or CD8 T cells. The T-cell activation pathway was also activated by CD8 T cells in three of five severe cases. Still, antiviral immune pathways were excessively expressed in the T cells of one severely and one mildly affected patient.
The severely sick patients also showed greater gene activation concerning B cell-mediated humoral immunity, complement activation, the Ig-mediated humoral immune response, and phagocytosis. This implies a more broad-based humoral immune response in severe illness, including a systemic pro-inflammatory process mediated by complement activation.
However, most of the adaptive immune cells failed to express pro-inflammatory cytokines, which may mean that in most cases, these reverted to normal once the patient recovered. The expression of mitogen-activated protein kinase (MAPK) pathway was profoundly decreased in all patients compared to controls, and this agrees with a previous study showing this to be a sign of recovery.
Specific T-cell Subsets Against SARS-CoV-2
The researchers found that all recovered patients showed the activity of IFN-γ-secreting or specific memory T cells in response to exposure to one or more of the ten groups of viral peptides. This is an experimental validation of specific T cell immunity being developed in these patients.
Each of the patients had a much higher proportion of such cells against the S peptides compared to any other. T cells in severely sick patients had 12 times the response to five or more viral proteins, but mildly ill patients had only 3.5 times the response, relative to baseline levels before stimulation.
This indicates that S-specific memory T cells, as well as those specific for other proteins, are produced and sustained by recovered patients. Another significant finding is that severely sick patients had a more robust immune response than mildly sick patients. This could mean that the former has better T cell memory against this virus than the latter.
The researchers sum up, “Taken together, these results denote that SPs and MPs may experience different cellular and humoral immune responses, which likely are related to different degrees of disease severity.”
The investigators found that the adaptive immune responses underwent a specific change in repertoire with the peripheral lymphocytes showing a different pattern of function and distribution. Severe patients appeared to have a stronger and sustained T and B cell response.
The results showed that three significant clusters of memory T cells appeared in the adaptive immune system. Peptides from the viral M protein induce the T cell response in most COVID-19 patients. The more severe the disease phenotype, the stronger the humoral and T-cell response was in the recovered patients.
The higher level of expression of such pathways indicates continuing active immunity after clinical symptom resolution, confirming that this illness requires longer recovery time for health to return. Both the composition and function of peripheral blood lymphocytes need to be further studied in detail to elucidate this aspect of recovery.
The presence of clonal expansion and overexpressed immune pathways in one mild patient, common to severe patients, may reflect the effect of coexisting hypertension and diabetes in this patient. This, in turn, could mean that adaptive immunity in COVID-19 is affected by certain chronic disease conditions.
IFN induction is not uniform in these patients. The B cell clone IGHV4-34 that is uncommon in IgG memory B cells in controls, is expressed at elevated levels in these patients. The presence of one TCR clone targeting a stromal antigen in human bone marrow is perhaps suggestive of an autoimmune phenomenon induced by the infection, which contributes to severe symptoms.
Thus, many viral peptides induce specific memory T cell responses in COVID-19 patients, including S and M. This suggests more targets for the development of vaccines. Moreover, the simultaneous detection of three major clusters of memory T cells in both mildly and severely ill patients seems to demonstrate that all patients develop a robust adaptive immunity against the virus.
Zhang, F. et al. (2020). Adaptive Immune Responses To SARS-Cov-2 Infection In Severe Versus Mild Individuals. Signal Transduction and Targeted Therapy volume 5, Article number: 156. https://www.nature.com/articles/s41392-020-00263-y