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42 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly 43 unfolding pandemic, overwhelming health care systems worldwide 1 . Clinical manifestations of 44 Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to 45 acute respiratory failure and death 2 , yet the underlying mechanisms for this high variability are 46 still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 47 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4 + T cell 48responses correlated with positive outcomes 3,4 , whereas T cell immune responses to SARS-49CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection 50and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4 + T cells in peripheral 51blood. We demonstrate the presence of S-reactive CD4 + T cells in 83% of COVID-19 patients, 52as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower 53 frequencies. Strikingly, S-reactive CD4 + T cells in COVID-19 patients equally targeted N-54terminal and C-terminal epitopes of S whereas in HD S-reactive CD4 + T cells reacted almost 55exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike 56 glycoprotein of human endemic "common cold" coronaviruses (hCoVs), and b) contains the S2 57 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane 58 domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4 + T 59 cells in HD, S-reactive CD4 + T cells from COVID-19 patients co-expressed CD38 and HLA-60DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-61CoV-2-reactive T cell responses providing critical tools for large scale testing and 62 characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of 63 pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high 64interest but larger scale prospective cohort studies are needed to assess whether their presence 65 is a correlate of protection or pathology for COVID-19. Results of such studies will be key for 66 a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment 67 methods and to support vaccine development.

The functional relevance of pre-existing cross-immunity to SARS-CoV-2 is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)-reactive and SARS-CoV-2-cross-reactive CD4+ T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that pre-existing spike- and S816-830-reactive T cells were recruited into immune responses to SARS-CoV-2 infection and their frequency correlated with anti-SARS-CoV-2-S1-IgG antibodies. Spike-cross-reactive T cells were also activated after primary BNT162b2 COVID-19 mRNA vaccination displaying kinetics similar to secondary immune responses. Our results highlight the functional contribution of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunization and the high rate of asymptomatic/mild COVID-19 disease courses.

Forming the outer body barrier, our skin is permanently exposed to pathogens and environmental hazards. Therefore, skin diseases are among the most common disorders. In many of them, the immune system plays a crucial pathogenetic role. For didactic and therapeutic reasons, classification of such immune-mediated skin diseases according to the underlying dominant immune mechanism rather than to their clinical manifestation appears to be reasonable. Immune-mediated skin diseases may be mediated mainly by T cells, by the humoral immune system, or by uncontrolled unspecific inflammation. According to the involved T cell subpopulation, T cell–mediated diseases may be further subdivided into T1 cell–dominated (e.g., vitiligo), T2 cell–dominated (e.g., acute atopic dermatitis), T17/T22 cell–dominated (e.g., psoriasis), and Treg cell–dominated (e.g., melanoma) responses. Moreover, T cell–dependent and -independent responses may occur simultaneously in selected diseases (e.g., hidradenitis suppurativa). The effector mechanisms of the respective T cell subpopulations determine the molecular changes in the local tissue cells, leading to specific microscopic and macroscopic skin alterations. In this article, we show how the increasing knowledge of the T cell biology has been comprehensively translated into the pathogenetic understanding of respective model skin diseases and, based thereon, has revolutionized their daily clinical management.

The prevailing ‘division of labor’ concept in cellular immunity is that CD8+ T cells primarily utilize cytotoxic functions to kill target cells, while CD4+ T cells exert helper/inducer functions. Multiple subsets of CD4+ memory T cells have been characterized by distinct chemokine receptor expression. Here, we demonstrate that analogous CD8+ memory T-cell subsets exist, characterized by identical chemokine receptor expression signatures and controlled by similar generic programs. Among them, Tc2, Tc17 and Tc22 cells, in contrast to Tc1 and Tc17 + 1 cells, express IL-6R but not SLAMF7, completely lack cytotoxicity and instead display helper functions including CD40L expression. CD8+ helper T cells exhibit a unique TCR repertoire, express genes related to skin resident memory T cells (TRM) and are altered in the inflammatory skin disease psoriasis. Our findings reveal that the conventional view of CD4+ and CD8+ T cell capabilities and functions in human health and disease needs to be revised.

BackgroundSARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases.MethodsAs part of a prospective cohort study, we investigated the induction, stability and boosting of vaccine-specific antibodies, B cells and T cells in patients with multiple sclerosis (MS) on different DMTs after homologous primary, secondary and booster SARS-CoV-2 mRNA vaccinations. Of 126 patients with MS analysed, 105 received either anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and 21 were untreated MS patients for comparison.ResultsIn contrast to all other MS patients, and even after booster, most aCD20-BCD- and fingolimod-treated patients showed no to markedly reduced anti-S1 IgG, serum neutralising activity and a lack of receptor binding domain-specific and S2-specific B cells. Patients receiving fingolimod additionally lacked spike-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether a humoral immune response was elicited.ConclusionsThe lack of immunogenicity under long-term fingolimod treatment demonstrates that functional immune responses require not only immune cells themselves, but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses suggests that fingolimod-treated patients with MS are at risk for severe SARS-CoV-2 infections despite booster vaccinations, which is highly relevant for clinical decision-making and adapted protective measures, particularly considering additional recently approved sphingosine-1-phosphate receptor antagonists for MS treatment.

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.

COVID-19, coronavirus disease 2019; d28, day 28 after first vaccination; d49, day 49 after first vaccination; ∼d28, around day 28 after COVID-19 symptom onset; ∼d49, around day 49 after COVID-19 symptom onset; ∼d94, around day 94 after COVID-19 symptom onset; RT-PCR, real-time PCR; S1, SARS-CoV-2 spike glycoprotein subunit 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S-I, peptide mix representing the SARS-CoV-2 spike glycoprotein N-terminal part; sIgA, secretory IgA; S-II, peptide mix representing the SARS-CoV-2 spike glycoprotein C-terminal part mix.