Partial STAT5 signaling is sufficient for CD4+ T cell priming but not memory formation.

Signal transducer and activator of transcription 5 (STAT5) plays an important role in regulating gene expression in response to cytokines of the common (γc) chain family. In this capacity, STAT5 promotes CD8+ effector and memory T cell survival and regulatory T cell development. However, its function in conventional CD4+ T cells is less clear. In this study, the requirement of intact STAT5 signaling for CD4+ effector and memory T cell generation and maintenance was investigated by using DO11.10 TCR transgenic T cells that are genetically deficient in STAT5A or B, as well as by transducing DO11 T cells with a dominant-negative STAT5 to temporally block STAT5 function. We found that the presence of STAT5A or B alone was sufficient for primary CD4+ effector T cell generation, but not for establishing a long-lived memory cell population. Similarly, blocking STAT5 signaling during priming did not prevent initial T cell activation, but inhibited the generation of memory cells. Surprisingly, blocking STAT5 post-priming did not impact the long-term survival of CD4+ memory T cells in vivo. Mechanistically, intact STAT5B, but not STAT5A, was required for IL-7Rα re-expression in activated T cells, which is an important cytokine receptor for CD4+ memory generation. These data show that fully functional STAT5 is essential to deliver an early, non-redundant signal for memory programming during the primary CD4+ T cell response, while partial STAT5 signaling is sufficient for effector differentiation. Our results have implications for the precise use of STAT5 inhibitors to timely inhibit memory T cell responses.

Broad induction of immunoregulatory mechanisms after a short course of anti-IL-7Rα antibodies in NOD mice.

BACKGROUND: Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing ß-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Rα antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Rα administration. RESULTS: Anti-IL-7Rα antibodies were administered to prediabetic NOD mice for 3 weeks and blood samples were taken at the end of treatment and 2 weeks later to analyze changes in T cell phenotypes in response to IL-7Rα blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+ and CD8+ T cells from anti-IL-7Rα-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+ T cells was increased at the end of anti-IL-7Rα antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Rα-treated mice were more sensitive to co-inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics. CONCLUSIONS: Together, our data show that short-term blockade of IL-7Rα induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Rα antibodies to modulate autoreactive T cell responses.

Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis.

OBJECTIVE: Immune dysfunction is an important component of the disease process underlying systemic sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. This study was undertaken to measure the expression and function of the coinhibitory receptors (co-IRs) programmed cell death 1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) in lymphocyte subsets from the peripheral blood of patients with SSc. METHODS: Co-IR expression levels on subsets of immune cells were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of SSc and healthy control peripheral blood mononuclear cells (PBMCs) in the presence of co-IR-blocking antibodies. Supernatants from cultures of stimulated PBMCs were added to SSc fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls. RESULTS: Levels of the co-IRs PD-1 and TIGIT were increased, and each was coexpressed, in distinct T cell subsets from SSc patients compared to healthy controls. Levels of TIM-3 were increased in SSc natural killer cells. PD-1, TIGIT, and TIM-3 antibody blockade revealed patient-specific roles of each of these co-IRs in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT and TIM-3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating that enhanced T cell exhaustion is present in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed the gene expression profile in SSc fibroblasts. CONCLUSION: The altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated cross-talk of immune cells and fibroblasts at sites of inflammation and/or fibrosis.

Role of proprioceptive information in movement programming and control in 5 to 11-year old children.

The role of proprioceptive inputs in the control of goal-directed movements was examined, by means of the tendon vibration technique, in 5 to 11-year old children performing a serial pointing task. Children pointed, with movements of various amplitudes and at various positions, by alternating wrist flexions and extensions. Tendon vibration was applied to both agonist and antagonist muscles to perturb relevant muscular proprioceptive inputs during the static or dynamic phase of the task, i.e., during stops on targets or during movement execution. Constant and variable amplitude errors as well as constant position error were evaluated. Vibratory perturbation applied during movement execution resulted in a similar reduction in movement amplitude, yielding an increased constant error in all age groups and a systematic position error in the direction of the movement starting point. Perturbing proprioception during static phases preceding movement resulted in an age-related increase in the variable amplitude error, which was maximal in 5-year old children performing extension movements. The results were interpreted in terms of the use of proprioceptive information in the feedforward and feedback based components of movement control in children. In particular, the results indicated (1) developmental changes in the relative weighting of each component, (2) an increased capacity to move from one strategy to the other, depending on the availability of information, and (3) developmental changes from an alternated to an integrated control of amplitude and position in serial pointing.

Aged-related differences in the attentional cost of pointing movements.

The aim of the present study was to analyze, in children aged 6, 8 and 11, the developmental trend of the attentional cost related to the programming and execution of pointing movements, using a dual-task paradigm. Our results showed that the attentional cost associated to the programming and the first phase of the pointing movement decreased non linearly with age, in particular a plateau between 8 and 11 was observed. This confirmed that the developmental trend of the control of pointing movements is characterized by a no monotonic evolution in which feedforward processes were predominantly used in the younger children, feedback processes were predominantly used in older children (since age 8), and one-line over feedforward processes were used in adults.

Age-related differences in the reaching and grasping coordination in children: unimanual and bimanual tasks.

This study examined age-related differences in the coordinative mechanism of the reach-to-grasp movement in three groups of children aged 6, 8, and 11 year, and in healthy adults. Three prehension conditions were manipulated: an unimanual and a bimanual self-driven tasks in which the reaching and grasping of the object were performed by participants, and a bimanual externally-driven task, in which the experimenter brought the object into the vicinity of the participant which grasped it. Classical kinematics data-peak velocities of the reaching and the grasping, the time to onset grip opening, maximum grip opening and grip closure-were calculated. Moreover, to obtain equivalent kinematics variables for all age groups, relative time to peak velocity (% of reaching duration), relative maximum grip opening (% of object size), and percentage of the four types of phase plans between reaching velocity and grip size have been calculated for each group of age. Our main results showed (1) a high variability at age 6, (2) an age-related change between the 6- and 8-year old for almost all of the dependent variables, and (3) a significant difference between the 11-year olds and adults. In summary, at 6 years, the interdependence between the reaching and grasping programs was unstable. A transitory feedback-based coordination between reaching and grasping appeared at 8 years of age. Finally, the adults' relationship between reaching and grasping was not attained at the age of 11.

Visuomanual coordination in childhood: adaptation to visual distortion.

The aim of the experiment was to study the adaptive capacities of children to perform drawing movements while being visually perturbed. Children aged 5-11 years and a group of adults drew diamonds via information provided through a computer screen. The screen display was either upright or rotated 180 degrees. Results showed that the absence of direct vision of the hand yielded more perturbation in the youngest group of children compared to all other groups. In spite of some initial difficulty, all children reached accurate control after five trials. When faced with spatial rotations of the visual field, youngsters were again more perturbed than others. All children showed the same rate of adaptation to visual rotations, but they differed on adaptive strategies. Five- and 7-year-olds shifted to a feedforward mode of control consisting of the production of a rapid gesture, followed by error evaluation in order to correct their next movement. Older children were characterised by a progressive integration of reafferent visual and proprioceptive information. It resulted in an increase in duration of strokes and reduced speed, meaning enhanced on-line retrieval of information. However, 9-year-old children experienced more difficulty recuperating sensory information during movement than 11-year-olds, and kept using error feedback. Finally, visuomanual coordination in children aged 11 years, while slightly differing from that of adults, was not yet totally mature.