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Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing. Asymmetrical cell division helps to maintain cellular heterogeneity in the T cell compartment. Here the authors examine the differential immune responses built by naive and virtual memory T cells from young and aged individuals, and explore the effect of mTOR inhibition on asymmetrical cell division and memory formation. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) maintain peripheral self-tolerance and limit immune mediated pathology. Like effector T cells, Tregs can specialize in TH1-dominated immune responses and co-express T-bet together with Foxp3. This allows for expression of CXCR3 and efficient homing to sites of TH1 responses. However, whether such functional specialization is paralleled by memory generation among Tregs is unknown. In this study, we investigated the ability of polyclonal Tregs to form functional memory in response to viral infection. Using adoptive transfer models to compare infection-experienced Tregs generated upon acute Lymphocytic Choriomeningitis Virus (LCMV) WE and Vaccinia Virus (VV) infections with naive Tregs, we observed no differences in their phenotype or their in vivo maintenance. When comparing functional properties of infection-experienced and naive Tregs, we found no differences in in vitro suppressive capacity nor in their ability to limit the effector response upon homologous, systemic or local re-challenge in vivo. Our results suggest that no functional Treg memory is generated in the context of systemic LCMV or VV infection, but we cannot rule out the possibility that the generation of Treg memory may be possible in other contexts. [ABSTRACT FROM AUTHOR]

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vβ5+ conventional T cells into iTreg cells. Using Vβ5-deficient mice, we show that these Vβ5+ iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vβ5-deficient mice compromises suppression of microbiota-dependent activation of CD8+ T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vβ2+ Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology. Viral infection transiently depletes T regulatory cells (Treg). Here the authors identify a compensatory induced Treg population, which is required to rapidly replenish the Treg niche and suppress microbiota-driven, virus-induced colitis. [ABSTRACT FROM AUTHOR]

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance. TIGIT is a lymphocyte co-inhibitory receptor that can limit type 1 and cytotoxic T cell responses and maintain immunological tolerance. Here the authors show that TIGIT also limits immune pathology during LCMV or influenza infections in mice by driving IL-10 expression without negatively affecting the viral load. [ABSTRACT FROM AUTHOR]

Type 1 regulatory T cells (Tr1 cells ) that produce interleukin 10 (IL-10) are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for the induction of IL-10 by Tr1 cells, but the molecular mechanisms that lead to the development of these cells remain unclear. Here we show that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which was induced by IL-27, acted in synergy with c-Maf to promote the development of Tr1 cells. After T cell activation under Tr1-skewing conditions, the AhR bound to c-Maf and promoted transactivation of the Il10 and Il21 promoters, which resulted in the generation of Tr1 cells and the amelioration of experimental autoimmune encephalomyelitis. Manipulating AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses. [ABSTRACT FROM AUTHOR]

The article focuses on a study which demonstrates that inflammation in rheumatoid arthritis induces conversion of a subset of Foxp3+ T-cells into interleukin-17–producing cells that lead to disease pathogenesis. Topics discussed include cell differentiation, factors contributing to the balance between regulatory T-cells and helper T-cells type 17, and the role of converted cells in bone destruction.