T cell receptors (TCRs) are protein complexes formed by six different polypeptides. In most T cells, TCRs are composed of αβ subunits displaying immunoglobulin-like variable domains that recognize peptide antigens associated with major histocompatibility complex molecules expressed on the surface of antigen-presenting cells. TCRαβ subunits are associated with the CD3 complex formed by the γ, δ, ε, and ζ subunits, which are invariable and ensure signal transduction. Here, we review how the expression and function of TCR complexes are orchestrated by several fine-tuned cellular processes that encompass (a) synthesis of the subunits and their correct assembly and expression at the plasma membrane as a single functional complex, (b) TCR membrane localization and dynamics at the plasma membrane and in endosomal compartments, (c) TCR signal transduction leading to T cell activation, and (d) TCR degradation. These processes balance each other to ensure efficient T cell responses to a variety of antigenic stimuli while preventing autoimmunity.

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Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen‐coated particles, a process thought to be exclusive of specialized antigen‐presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR‐driven and mechanistically dependent on the GTPase RhoG. Using Rhog ^−/− mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high‐affinity class‐switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum–antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1–3 μm size antigen particles to follicular B cells.

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR’s CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low–molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC₅₀ (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell–mediated autoimmune and inflammatory diseases.

A correct identification of seropositive individuals for the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is of paramount relevance to assess the degree of protection of a human population to present and future outbreaks of the COVID‐19 pandemic. We describe here a sensitive and quantitative flow cytometry method using the cytometer‐friendly non‐adherent Jurkat T‐cell line that stably expresses the full‐length native spike “S” protein of SARS‐CoV‐2 and a truncated form of the human EGFR that serves a normalizing role. S protein and huEGFRt coding sequences are separated by a T2A self‐cleaving sequence, allowing to accurately quantify the presence of anti‐S immunoglobulins by calculating a score based on the ratio of fluorescence intensities obtained by double‐staining with the test sera and anti‐EGFR. The method allows to detect immune individuals regardless of the result of other serological tests or even repeated PCR monitoring. As examples of its use, we show that as much as 28% of the personnel working at the CBMSO in Madrid is already immune. Additionally, we show that anti‐S antibodies with protective neutralizing activity are long‐lasting and can be detected in sera 8 months after infection.

CCR5 is not only a coreceptor for HIV‐1 infection in CD4 ⁺ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T‐cell antigen receptor (TCR) nanoclustering in antigen‐experienced mouse and human CD4 ⁺ T cells. This activity is CCR5‐specific and independent of CCR5 co‐stimulatory activity. CCR5‐deficient mice showed reduced production of high‐affinity class‐switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD4 ⁺ T‐cell response. This study identifies a CCR5 function in the generation of CD4 ⁺ T‐cell memory responses and establishes an antigen‐independent mechanism that regulates TCR nanoclustering by altering specific lipid species.