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Regulatory T-cells (Tregs) are vital for maintaining immunological self-tolerance, and the transcription factor FOXP3 is considered critical for their development and function. Peripheral Treg induction may significantly contribute to the total Treg pool in healthy adults, and this pathway may be enhanced in thymic-deficient conditions like multiple sclerosis (MS). Here, we evaluated iTreg formation from memory versus naïve CD4(+)CD25(-) T-cell precursors. We report the novel finding that memory T-cells readily expressed CD25 and FOXP3, and demonstrated significantly greater suppressive function. Additionally, the CD25(-)FOXP3(-) fraction of stimulated memory T-cells also displayed robust suppression not observed in naïve counterparts or ex vivo resting (CD25(-)) T-cells. This regulatory population was present in both healthy subjects and clinically-quiescent MS patients, but was specifically deficient during disease exacerbation. These studies indicate that iTreg development and function are precursor dependent. Furthermore, MS quiescence appears to correlate with restoration of suppressive function in memory-derived CD4(+)CD25(-)FOXP3(-) iTregs.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27-, CD45RO-) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS.

Objectives We evaluated and compared the peripheral blood findings in patients with acute COVID-19 vs other viral respiratory infections. Methods We retrospectively reviewed peripheral blood counts and smear morphology in patients with a positive viral respiratory panel (VRP) or SARS-CoV-2 test. Results A total of 97 peripheral blood samples (COVID-19 infection, 53; VRP positive, 44) from 50 patients (mean [SD] age, 45.8 [20.8] years; females 52%) were reviewed. There were no statistically significant differences in the demographic characteristics between the 2 groups. The most common peripheral blood abnormalities were anemia, thrombocytopenia, absolute lymphopenia, and reactive lymphocytes. The following peripheral blood findings were significantly associated with other viral respiratory infections compared with COVID-19 infection: low red blood cell count, low hematocrit, high mean corpuscular volume, thrombocytopenia, low mean platelet volume, high red cell distribution width, band neutrophilia, and toxic granulation in neutrophils. Conclusions Our study showed that there are several peripheral blood count and morphologic abnormalities seen in patients with COVID-19, but most of these findings lack specificity as they are also seen in the other viral respiratory infections. [ABSTRACT FROM AUTHOR]

CD4+ T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4+ T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies. [ABSTRACT FROM AUTHOR]

Objective: Despite successful endovascular therapy, a proportion of stroke patients exhibit long‐term functional decline, regardless of the cortical reperfusion. Our objective was to evaluate the early activation of the adaptive immune response and its impact on neurological recovery in patients with large vessel occlusion (LVO). Methods: Nineteen (13 females, 6 males) patients with acute LVO were enrolled in a single‐arm prospective cohort study. During endovascular therapy (EVT), blood samples were collected from pre and post‐occlusion, distal femoral artery, and median cubital vein (controls). Cytokines, chemokines, cellular and functional profiles were evaluated with immediate and follow‐up clinical and radiographic parameters, including cognitive performance and functional recovery. Results: In the hyperacute phase (within hours), adaptive immune activation was observed in the post‐occlusion intra‐arterial environment (post). Ischemic vascular tissue had a significant increase in T‐cell‐related cytokines, including IFN‐γ and MMP‐9, while GM‐CSF, IL‐17, TNF‐α, IL‐6, MIP‐1a, and MIP‐1b were decreased. Cellularity analysis revealed an increase in inflammatory IL‐17+ and GM‐CSF+ helper T‐cells, while natural killer (NK), monocytes and B‐cells were decreased. A correlation was observed between hypoperfused tissue, infarct volume, inflammatory helper, and cytotoxic T‐cells. Moreover, helper and cytotoxic T‐cells were also significantly increased in patients with improved motor function at 3 months. Interpretation: We provide evidence of the activation of the inflammatory adaptive immune response during the hyperacute phase and the association of pro‐inflammatory cytokines with greater ischemic tissue and worsening recovery after successful reperfusion. Further characterization of these immune pathways is warranted to test selective immunomodulators during the early stages of stroke rehabilitation. [ABSTRACT FROM AUTHOR]