Follicular helper T (T
) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether T
cells were decreased by costimulation blockade ...using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)
T
cells and other ICOS
populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment T
profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS
T
cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, T
analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.
Lack of well‐trained Sudanese immunologists hampers the ability of next generation of Sudanese students to get quality immunology training. By narrating my personal story, I highlight the challenges ...faced by students at home and argue for the importance of mentorship in helping them realize their dreams.
The vast majority of Foxp3
regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the ...development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3
Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3
xRAG1
reporter mice revealed that the IL-1R2
Tregs are mainly RAG1
and CCR6
CCR7
, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2
Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2
Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25
Foxp3
tTregs and an accumulation of CD25
Foxp3
Treg precursors. Interestingly, the addition of IL-1R2
Tregs, but not IL-1R2
Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2
Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.
Lack of well‐trained Sudanese immunologists hampers the ability of next generation of Sudanese students to get quality immunology training. By narrating my personal story, I highlight the challenges ...faced by students at home and argue for the importance of mentorship in helping them realize their dreams.
Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is ...impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.
During influenza A virus (IAV) infections, CD4+ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression ...of T-box transcription factor 21 (T-bet) in Foxp3+ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4+ to CD8+ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet+ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated Tbx21 locus, similarly as in T-bet+ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the Foxp3 locus. In summary, our data suggest that T-bet+ but not T-bet− Tregs are epigenetically stabilized during IAV-induced infection in the lung.
Seasonal influenza outbreaks, especially in high-risk groups such as the elderly, represent an important public health problem. Prevailing inadequate efficacy of seasonal vaccines is a crucial ...bottleneck. Understanding the immunological and molecular mechanisms underpinning differential influenza vaccine responsiveness is essential to improve vaccination strategies. Here we show comprehensive characterization of the immune response of randomly selected elderly participants (≥ 65 years), immunized with the adjuvanted influenza vaccine Fluad. In-depth analyses by serology, multi-parametric flow cytometry, multiplex and transcriptome analysis, coupled to bioinformatics and mathematical modelling, reveal distinguishing immunological and molecular features between responders and non-responders defined by vaccine-induced seroconversion. Non-responders are specifically characterized by multiple suppressive immune mechanisms. The generated comprehensive high dimensional dataset enables the identification of putative mechanisms and nodes responsible for vaccine non-responsiveness independently of confounding age-related effects, with the potential to facilitate development of tailored vaccination strategies for the elderly.
Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 ...as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT
+
cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT
-
cTfh counterparts, and showed reduced capacity to help B cells
in vitro
. Additionally, TIGIT
+
cTfh expressed lower levels of CD40L than TIGIT
-
cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.
Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes ...the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.
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