Follicular Th (TFH) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5highPD-1high CD4+ TFH cells that exhibit TFH features (including Batf, Bcl6, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal TFH cells fail to expand and to acquire a full-blown GC TFH phenotype, as reflected by a higher ratio of GC TFH/non-GC CD4+ T cells in immunized adults than neonates (3.8 × 10−3 versus 2.2 × 10−3, p = 0.01). Following the adoptive transfer of naive adult OT-II CD4+ T cells, OT-II TFH cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4+ OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell–intrinsic factors. Postponing immunization to later in life increases the number of TFH cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC TFH and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the TFH cell development limits early life GC responses and that adjuvants/delivery systems supporting TFH differentiation may restore adultlike early life GC B cell responses.

IMPORTANCEThe SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses.OBJECTIVE To determine T-cell responses to the Omicron spike protein in anti-CD20-treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination. DESIGN, SETTING, AND PARTICIPANTSIn this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis.INTERVENTIONS Blood sampling before and 1 month after the third vaccine dose.MAIN OUTCOMES AND MEASURES Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose. RESULTSOf 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain. CONCLUSIONS AND RELEVANCEIn this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell-depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

Butyrophilins are proteins secreted during lactation and thought to influence immune function. Sarter et al. generated butyrophilin-2a2–deficient mice to show enhanced effector T cell responses, antitumor responses, and exacerbated EAE due to the impaired APC modulation of T cell immunity.

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.

Importance: The SARS-CoV-2 variant Omicron escapes neutralizing antibody responses elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third dose of vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. Objective: To determine T-cell responses to the Spike (S)-protein of Omicron in anti-CD20 treated patients before and after their third mRNA COVID-19 vaccination Design: Prospective observational monocentric study Setting: Conducted since March 2021 at the University Hospital Geneva Participants: Twenty adults with multiple sclerosis on anti-CD20 treatment (ocrelizumab) who received their third dose of mRNA COVID-19 vaccine 6 to 7 months after their second vaccination. Intervention: Blood sampling before and one month after the third vaccine dose Main outcomes and measures: Quantification of CD4 and CD8 (cytotoxic) T cells specific for SARS-CoV-2 S-protein of vaccine strain, Delta and Omicron variants , using activation marker induced assay (AIM) and comparing frequencies before and after the third vaccine dose. Results: S-specific CD4 and CD8 T-cell memory against all variants was maintained in around half of the patients six months after their second vaccination, albeit at lower frequencies against Delta and Omicron variants. A third dose enhanced the number of responders to all variants and significantly increased CD8 T-cell responses. The frequencies of T cells specific to Omicron and Delta remained lower than those specific to the vaccine strain after the boost. Conclusion and relevance: Vaccinated MS patients on anti-CD20 treatment show robust T-cell responses that recognize S from the circulating Delta and Omicron variants. Response rates increased after the third dose, demonstrating that a booster dose might improve cytotoxic T-cell mediated protection against severe disease in patients with low humoral response. The clinical relevance of the reduced frequencies of T cells specific to Omicron will need to be monitored in the future.

Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8+ T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC), which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8) is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.

Pertussis is still observed in many countries despite of high vaccine coverage. Acellular pertussis (aP) vaccination is widely implemented in many countries as primary series in infants and as boosters in school-entry/adolescents/adults (including pregnant women in some). One novel strategy to improve the reactivation of aP-vaccine primed immunity could be to include genetically- detoxified pertussis toxin and novel adjuvants in aP vaccine boosters. Their preclinical evaluation is not straightforward, as it requires mimicking the human situation where T and B memory cells may persist longer than vaccine-induced circulating antibodies. Toward this objective, we developed a novel murine model including two consecutive adoptive transfers of the memory cells induced by priming and boosting, respectively. Using this model, we assessed the capacity of three novel aP vaccine candidates including genetically-detoxified pertussis toxin, pertactin, filamentous hemagglutinin, and fimbriae adsorbed to aluminum hydroxide, supplemented—or not—with Toll-Like-Receptor 4 or 9 agonists (TLR4A, TLR9A), to reactivate aP vaccine-induced immune memory and protection, reflected by bacterial clearance. In the conventional murine immunization model, TLR4A- and TLR9A-containing aP formulations induced similar aP-specific IgG antibody responses and protection against bacterial lung colonization as current aP vaccines, despite IL-5 down-modulation by both TLR4A and TLR9A and IL-17 up-modulation by TLR4A. In the absence of serum antibodies at time of boosting or exposure, TLR4A- and TLR9A-containing formulations both enhanced vaccine antibody recall compared to current aP formulations. Unexpectedly, however, protection was only increased by the TLR9A-containing vaccine, through both earlier bacterial control and accelerated clearance. This suggests that TLR9A-containing aP vaccines may better reactivate aP vaccine-primed pertussis memory and enhance protection than current or TLR4A-adjuvanted aP vaccines.

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