The role of T cell immunity in COVID-19

Adaptive immunity is an essential part of the control of viral infections. There are two major arms of the adaptive immune system, consisting of B cells—the cells mainly producing antibodies—and T cells, which further separate into the CD4+ help T cells and the CD8+ cytotoxic T cells. While the main function of CD4+ T cells is the provision of help to antibody optimization by B cells and to activate CD8+ T-cells, CD8+ T cells provide a cytotoxic effect on infected cells. Since its first appearance in 2019, the SARS-CoV-2 virus and following COVID-19 disease have received extraordinary attention. An extensive body of work evaluates the function and kinetic of adaptive immunity on COVID-19. Here we review the role of T cells in COVID-19 and their role in disease severity. © 2023 Elsevier Inc. All rights reserved.

DIFFERENT HUMORAL but SIMILAR CELLULAR RESPONSES of PATIENTS with AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES under DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS after COVID-19 VACCINATION

Background: The interplay between humoral and cellular response after vaccination against SARS-CoV-2 in patients (pts.) with autoimmune infammatory rheumatic diseases (AIRD) remains unknown. Objectives: To investigate the impact of different immunosuppressive therapies on the development of humoral and cellular immune responses to full 2-dose SARS-CoV-2 vaccination in AIRD pts. with stable low disease activity. Methods: The immune reactivity to COVID-19 vaccination was investigated in a prospectively recruited AIRD cohort with rheumatoid arthritis, axial spondy-loarthritis or psoriatic arthritis which received a therapy with IL-17i, TNFi, JAKi or MTX (alone or in combination). Almost all patients received mRNA-based vaccine, only 4 patients had a heterologous scheme. Anti-spike(S) antibodies(ab.) and sera neutralizing capacity (neutralization dilution 50;ND50) were measured 4 weeks after the frst (prime+4w) and 4 weeks after the second vaccination (boost+4w). Vaccine-specifc cellular immunity was evaluated by quantifying expression of activation markers on T cells as well as their production of key cytokines, at prime+4w and boost+4w. Results: Overall, a total of 92 pts. were included in the fnal cohort. 31 (33.7%) pts. were on TNFi, 24 (26.1%) on IL-17i, 24 (26.1%) on JAKi, each group encompassing pts. receiving drug inhibitors alone or in combination with MTX.13 (14.1%) were treated with MTX alone. The median time between the vaccination and blood sampling was 31 [IQR: 28-34] days after prime+4w and 28 [IRQ: 28-28] days after boost+4w. Although at prime+4w only 34/90 (37.8%) of pts. presented neutralizing ab., the majority (86/91, 94.5%), developed them at boost+4w. The highest neutralization titer developed the pts. on IL-17i both at prime+4w (74 [IQR: 13-91]) and boost+4w (798 [IQR: 511-1344]), while no statistically signifcant differences were found in the neutralization titer at boost+4w for the TNFi, JAKi, and MTX groups: 207 ND50 [IQR: 120-576], 319 [IQR: 133-461] and 749 [IQR: 264-1920], respectively. 81/90 (90.0%) pts. developed IgG ab. against SARS-CoV-2 S-protein at prime+4w and 91/92 (98.9%) at boost+4w. Pts. receiving IL-17i developed higher ab. titers (8295 U/mL [IQR: 4586-11,237]) compared to the other three groups: JAKi (4405 U/mL [IQR: 1436-7265], TNFi (2313 [IQR: 1156-3630] U/mL) and MTX (2010 U/mL [IQR: 693-9254]). Neutralization capacity correlated well with the titer of anti-S ab. at both timepoints. Co-administration of biologic/tsDMARDs and MTX led to lower titers compared to biologic/tsDMARDs mon-otherapy. All therapies left frequencies of CD154+CD137+ CD4+ T cells and CD137+ CD8+ T cells at prime+4w and boost+4w unchanged. Polyfunction-ality and T cell cytokine profiles across therapies did not signifcantly vary at boost+4w. Conclusion: Even after insufficient seroconversion for neutralizing capacity and ab. response against SARS-CoV-2 S-proteins between pts. of different mod of action agents, particularly for MTX and JAKi after frst vaccination, a second vaccination covered almost all pts. regardless of DMARDs therapy, with better outcomes in those on IL-17I. T cell immunity revealed similar frequencies of activated T cells in all modes of action after the second vaccination.

Allograft infiltration and meningoencephalitis by sars-cov-2 in a pancreas-kidney transplant recipient

Introduction: COVID-19 primarily affects epithelia of the upper and lower respiratory tract. Thus, impairment of kidney function has been primarily attributed to secondary effects like cytokine release or fluid balance disturbances so far. Methods: We provide evidence that SARS-CoV-2 can directly infiltrate a kidney allograft. Results: A 69-year old male pancreas-kidney transplant recipient presented to our hospital with COVID-19 pneumonia and impaired pancreas and kidney allograft function. Kidney biopsy was performed showing tubular damage and an interstitial mononuclear cell infiltrate. RT-PCR from the biopsy specimen was positive for SARS-CoV-2, while being negative in a peripheral blood sample. Subsequently, he suffered from two convulsive seizures. Magnetic resonance tomography suggested meningoencephalitis, which was confirmed by SARS-CoV-2 RNA transcripts in the cerebrospinal fluid. Conclusion: The present case demonstrates that SARS-CoV-2 can infiltrate diverse organs. The patient suffered from COVID-19 pneumonia, meningoencephalitis and nephritis. SARS-CoV-2 binds to its target cells through angiotensin-converting enzyme 2, which is expressed in a broad variety of tissues including the lung, brain and kidney. SARS-CoV-2 thereby shares features with other human coronaviruses including SARS-CoV that were identified as pathogens beyond the respiratory tract as well. The present case should provide awareness that extrapulmonary symptoms in COVID-19 may be attributable to viral infiltration of diverse organs.

Monitoring of general immune status and sars-cov-2 reactive t-cell and humoral immunity facilitates the clinical decision in a severe sars-cov-2-associated pneumonia, meningoencephalitis and gastroenteritis in a pancreas-kidney transplant patient

Introduction: The optimal management in transplant recipients with COVID-19 remains uncertain. The main concern is the ability of immunosuppressed patients to generate sufficient immunity for antiviral protection. Methods: Here, we report on immune monitoring facilitating a successful outcome of severe SARS-CoV-2-associated pneumonia, meningoencephalitis, gastroenteritis and acute kidney and pancreas graft failure in a pancreaskidney transplant recipient. Results: Despite the verylownumbersof circulating B-,NK,andT-cells identified in follow up, a strong SARS-CoV-2 reactive T-cell response was observed. Importantly, we detected T cells reactive to Spike,Membrane and Nucleocapsid proteins of SARS-CoV-2 with majority of T-cells showing polyfunctional proinflammatory Th1 phenotype with advanced differentiation stage at all analyzed time points. Antibodies against Spike protein were also detected with increasing titers in follow up. A correlation between cellular and humoral immunity was observed underscoring the specificity of demonstrated data. Conclusion: We conclude that analyzing the kinetics of non-specific and SARS-CoV-2-reactive cellular and humoral immunity can facilitate the clinical decision on immunosuppression adjustment and allow successful outcome as demonstrated in the current clinical case. While the antiviral protection of the detected SARS-CoV-2-reactive T-cells requires further evaluation, our data prove an ability mounting a strong SARS-CoV-2-reactive T-cell response with functional capacity in immunosuppressed patients.

Transplant patients are able to mount sars-cov-2-reactive t-cell response with the magnitude and functionality comparable to non-immunosuppressed patients

Introduction: The optimal management of COVID-19 in transplant patients is not defined so far. The major concern is the ability of transplant patients to generate a sufficient antiviral response under immunosuppressive treatment. Methods: Here, we analysed T-cell immunity directed against Spike, Membrane and Nucleocapsid proteins of SARS-CoV-2 in a small cohort of 6 transplant patients (TP) with COVID-19 in comparison to 28 non-immunosuppressed patients (NIP). Results: The median patient age of transplant cohort (3 renal transplant, 1 lung, and 1 combined liver-kidney and 1 pancreas-kidney) as well as gender did not differ from NIP. We also did not find statistical differences for the time between the diagnosis of COVID-19 and analysis of T-cell immunity between the two cohorts. Notably, despite immunosuppressive therapy, we were able to detect a strong antiviral response in transplant patients. TP generated SARSCoV-2 reactive T-cells against all three proteins with predominance of CD4 + T cells with pro-inflammatory Th1 phenotype. Moreover, SARS-CoV-2 reactive CD4 + and CD8 + T cells were able to produce multiple pro-inflammatory cytokines demonstrating their potential protective capacity. Of interest, the frequencies and cytokine production patterns of SARS-CoV-2 reactive T-cells did not show any differences between TP and NIP. Conclusion: A strong polyfunctional T-cell response directed against all three SARS-CoV-2 proteins can be generated in transplant despite immunosuppressive treatment. In comparison to non-immunosuppressed patients, the antiviral immunity is non-inferior. Since the dosage of immunosuppression in analysed patients was reduced, further studies are required to assess the antiviral immunity under standard immunosuppression.

Pre-existing sars-cov-2 reactive t cells in renal transplant patients

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused unprecedented public health and economical challenges worldwide. Cellular immunity is known to be crucial for the virus clearance. Recent data demonstrate pre-existing SARS-CoV-2-reactive T cells in samples of healthy blood donors collected before SARS-CoV-2 pandemics. The presence of these potentially protective T cells in SARS-CoV-2 naive population can be explained by cross-reactivity to the endemic common cold coronavirus. Whether such cells are also detectable in immunosuppressed patients is not known so far. Methods: We analysed the presence of SARS-CoV-2-cross-reactive T cell immunity in samples of 10 renal transplant patients (RTX) collected in 2019 before the onset of SARS-CoV-2 pandemics. Samples of 10 non-immunosuppressed/ immune competent SARS-CoV-2 naive patients matched to transplant patients were analysed as controls. T-cell reactivity against Spike-, Nucleocapsid-, and Membrane-SARS-CoV-2 proteins were analysed by multiparameter flow cytometry. Results: 50% of analysed RTX showed CD4 + T-cells reactive against at least one SARS-CoV-2 protein. CD8 + T cells reactive against at least one SARSCoV2 protein were demonstrated in 30% of RTX. Notably, the detected cells were of differentiated memory phenotype producing several Th1 cytokines including IFNg, TNFa, IL-2, as well as Granzyme B. The frequencies and cytokine expression pattern of SARS-CoV-2 reactive T-cells did not differ between transplant and non-transplant cohorts. Conclusion: Despite immunosuppressive treatment and underlined renal disease, transplant patients were able to generate cellular immunity crossreactive to SARS-CoV-2. The magnitude and functionality of the pre-existing immunity was non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection.