Cross-reactive T cells aid in the fight: There is mounting evidence that immunological memory after infection with seasonal human coronaviruses (hCoVs) contributes to cross-protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Loyal et al . identified a universal immunodominant coronavirus peptide found within the fusion peptide domain of coronavirus spike protein. This peptide is recognized by CD4 ⁺ T cells in 20% of unexposed individuals, more than 50% of SARS-CoV-2 convalescents, and 97% of subjects treated with the Pfizer–BioNTech COVID-19 vaccine. Although ubiquitous, these coronavirus-reactive T cells decreased with age, which may explain in part the increased susceptibility of elderly people to COVID-19. —STS

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

Advanced age is a main risk factor for severe COVID-19. However, low vaccination efficacy and accelerated waning immunity have been reported in this age group. To elucidate age-related differences in immunogenicity, we analyzed human cellular, serological, and salivary SARS-CoV-2 spike glycoprotein-specific immune responses to the BNT162b2 COVID-19 vaccine in old (69–92 y) and middle-aged (24–57 y) vaccinees compared with natural infection (COVID-19 convalescents, 21–55 y of age). Serological humoral responses to vaccination excee-ded those of convalescents, but salivary anti-spike subunit 1 (S1) IgA and neutralizing capacity were less durable in vaccinees. In old vaccinees, we observed that pre-existing spike-specific CD4⁺ T cells are associated with efficient induction of anti-S1 IgG and neutralizing capacity in serum but not saliva. Our results suggest pre-existing SARS-CoV-2 cross-reactive CD4⁺ T cells as a predictor of an efficient COVID-19 vaccine-induced humoral immune response in old individuals. Key Points Vaccination efficiency is associated with pre-existing CD4⁺ T cells in the elderly. Salivary IgA response is less durable in COVID-19 vaccinees than in convalescents.

T cells and their effector functions, in particular the canonical cytotoxicity of CD8 ⁺ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8 ⁺ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8 ⁺ T cells expressed CD40L, and conditional CD40L ablation in CD8 ⁺ T cells alone led to tumor formation. Mechanistically, CD40L ⁺ CD8 ⁺ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling–induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8 ⁺ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.

Disease-modifying therapies (DMTs) are widely used in neuroimmunological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Although these treatments are known to predispose patients to infections and affect their responses to vaccination, little is known about the impact of DMTs on the myeloid cell compartment. In this study, we use mass cytometry to examine DMT-associated changes in the innate immune system in untreated and treated patients with MS (n = 39) or NMOSD (n = 23). We also investigated the association between changes in myeloid cell phenotypes and longitudinal responsiveness to homologous primary, secondary, and tertiary SARS-CoV-2 mRNA vaccinations. Multiple DMT-associated myeloid cell clusters, in particular CD64⁺HLADR^low granulocytes, showed significant correlations with B and T cell responses induced by vaccination. Our findings suggest the potential role of myeloid cells in cellular and humoral responses following vaccination in DMT-treated patients with neuroimmunological diseases.

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.