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Antibodies play a crucial role in virus control. The production of antibodies requires virus-specific B cells to encounter viral antigens in lymph nodes, become activated, interact with different immune cells, proliferate and enter specific differentiation programmes. Each step occurs in distinct lymph node niches, requiring a coordinated migration of B cells between different subcompartments. The development of multiphoton intravital microscopy has enabled researchers to begin to elucidate the precise cellular and molecular events by which lymph nodes coordinate humoral responses. This Review discusses recent studies that clarify how viruses interfere with antibody responses, highlighting how these mechanisms relate to our topological and temporal understanding of B cell activation within secondary lymphoid organs.

Differentiation of CD4 + T cells into either follicular helper T (T FH ) or type 1 helper T (T H 1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4 + T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove T FH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T H 1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4 + T cell differentiation and might instruct vaccine design strategies. Iannacone and colleagues show that the spatiotemporal regulation of type I interferon expression shapes the differentiation of antiviral CD4 + T cells into T FH or T H 1 cells.

Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8 + T cells are essential for combating severe infections, whereas CD4 + T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies. Here the authors use three different mouse models to show that prior infection or mRNA vaccination can protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) independently of antibodies, highlighting the importance of T cell-derived interferon-γ (IFN-γ) in host defense and the need to consider this measure of protection in vaccination.

Protection from viral infections depends on immunoglobulin isotype switching, which endows antibodies with effector functions. Here, we find that the protein kinase DYRK1A is essential for B cell-mediated protection from viral infection and effective vaccination through regulation of class switch recombination (CSR). Dyrk1a -deficient B cells are impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identify MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site impaired CSR. After CSR and germinal center (GC) seeding, DYRK1A is required for attenuation of B cell proliferation. These findings demonstrate DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for therapeutic manipulation in antibody-mediated autoimmunity. Class switch recombination (CSR) is a process by which B cells switch their immunoglobulin isotype and develop pathogen-eliminating antibodies. Here, the authors show that a protein kinase DYRK1A is required for protection from viral infection through the regulation of CSR and effective clonal expansion.

The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation. The lysine-specific histone demethylase 1 A (LSD1) can regulate cytotoxic CD8 T cell (CTL) responses and anti-tumor immunity. Here the authors show that ex vivo epigenetic reprogramming with a LSD1 inhibitor enhances cell persistence and anti-tumor activity of adoptively transferred CD8 T cells in preclinical tumor models.

miR-21 is highly expressed in iNKT and activated T cells, but its T-cell autonomous functions are poorly defined. We sought to investigate the role of miR-21 in the development and functions of T and iNKT cells, representing adaptive and innate-like populations, respectively. We studied mice with a conditional deletion of miR-21 in all mature T lymphocytes. Thymic and peripheral T and iNKT compartments were normal in miR-21 KO mice. Upon activation , miR-21 depletion reduced T-cell survival, T 17 polarisation and, remarkably, T- and iNKT cell ability to respond to low-affinity antigens, without altering their response to high-affinity ones. Mechanistically, miR-21 sustained CD28-dependent costimulation pathways required to lower the T-cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T-cell sensitivity to antigenic stimulation and survival. Upon immunisation with the low-affinity self-epitope MOG , miR-21 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T-cell responses against high-affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection. The induction of T-cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR-21 sustains CD28 costimulation, decreasing the T-cell activation threshold and increasing their sensitivity to antigenic stimulation and survival, broadening the immune surveillance range. This occurs at the cost of unleashing autoimmunity, resulting from the recognition of weak self-antigens by autoreactive immune responses. Thus, miR-21 fine-tunes T-cell response and self-/non-self-discrimination.

A genetic variant of the protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with a wide range of autoimmune diseases; however, the reasons behind its prevalence in the general population remain not completely understood. Recent evidence highlights an important role of autoimmune susceptibility genetic variants in conferring resistance against certain pathogens. In this study, we examined the role of PTPN22 in persistent infection in mice lacking PTPN22 infected with lymphocytic choriomeningitis virus clone 13. We found that lack of PTPN22 in mice resulted in viral clearance 30 days after infection, which was reflected in their reduced weight loss and overall improved health. PTPN22 mice exhibited enhanced virus-specific CD8 and CD4 T cell numbers and functionality and reduced exhausted phenotype. Moreover, mixed bone marrow chimera studies demonstrated no differences in virus-specific CD8 T cell accumulation and function between the PTPN22 and PTPN22 compartments, showing that the effects of PTPN22 on CD8 T cells are T cell-extrinsic. Together, these findings identify a CD8 T cell-extrinsic role for PTPN22 in weakening early CD8 T cell responses to collectively promote persistence of a chronic viral infection.

Pathogen recognition by dendritic cells (DC) is crucial for the initiation of both innate and adaptive immune responses. Activation of Toll-like Receptors (TLRs) by microbial molecular patterns leads to the maturation of DC, which present the antigen and activate T cells in secondary lymphoid tissues. Cytokine production by DC is critical for shaping the adaptive immune response by regulating T helper cell differentiation. It was previously shown by our group that Src kinases play a key role in cytokines production during TLR4 activation in human DC. In this work we investigated the role of Src kinases during different TLRs triggering in human monocyte-derived DC (MoDC). We found that Src family kinases are important for a balanced production of inflammatory cytokines by human MoDC upon stimulation of TLR3 and 8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the DC maturation pattern. In particular, while expression of IL-12 and other inflammatory cytokines depend on Src kinases, the induction of IL-23 and co-stimulatory molecules do not. Accordingly, DC treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the Th17 subset survival but are less efficient in inducing Th1 differentiation. We suggest that the pharmacological modulation of DC maturation has the potential to shape the quality of the adaptive immune response and could be exploited for the treatment of inflammation-related diseases.

The responses of CD8 + T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8 + T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8 + T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8 + T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8 + T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection. CD8 + T cells that are primed by hepatocytes differentiate into dysfunctional T cells, which can be rescued by treatment with IL-2.

An efficient immune response requires coordination between innate and adaptive immunity, which act through cells different in origin and function. Here we report the identification of thymus-derived αβ-T-cell receptor + cells that express CD11c and major histocompatibility complex class II, and require FLT3 ligand for development (T DC ). T DC express genes heretofore found uniquely in T cells or dendritic cells, as well as a distinctive signature of cytotoxicity-related genes. Unlike other innate T-cell subsets, T DC have a polyclonal T-cell receptor repertoire and respond to cognate antigens. However, they differ from conventional T cells in that they do not require help from antigen-presenting cells, respond to Toll-like receptor-mediated stimulation by producing interleukin-12 and process and present antigen. The physiological relevance of T DC , found in mice and humans, is still under investigation, but the fact that they combine key features of T and dendritic cells suggests that they provide a bridge between the innate and adaptive immune systems. The division of the immune system into innate and adaptive arms has become blurred in recent years. Kuka et al. identify a novel population of αβ-T-cell receptor-expressing cells in mice and humans that both presents and responds to antigen and produces interleukin-12, thus exhibiting core properties of both dendritic cells and T cells.