Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR‐transgenic Tregs

Abstract

The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.

Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial

“…IL-2, another T-cell cytokine, regulates T-cell proliferation, including T regs , which in turn regulate Th17 cells[41]. In our multiple regression model (Table 6), IL-17α was a positive predictor for an increased O 2 requirement at ICU discharge in the placebo group, potentially indicating a proinflammatory role for IL-17α.…”

Lung-Infiltrating Foxp3+ Regulatory T Cells Are Quantitatively and Qualitatively Different during Eosinophilic and Neutrophilic Allergic Airway Inflammation but Essential To Control the Inflammation

“…Treg cells are a highly proliferative population in vivo, and ~20% of LN Treg cells are shown in active cell cycle (40, 41). Treg cells in the lung tissues expressed high levels (~80%) of Ki-67, which is in stark contrast with the proportion of cycling Treg cells in the medLN (30~40% Ki-67+) (Fig 7A).…”

A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2–Dependent Regulatory T Cells in the Spleen

“…While critically important for intestinal T r cell homeostasis (53), enhanced frequencies and intact Il-2 activation amongst circulating T r cells from gnotobiotic mice demonstrate microbial-derived antigens are not required for the production of T r cell-supportive Il-2 (54). Interrogating the role of “self” antigens in the generation of homeostatic Il-2 has relied heavily on TCR-transgenic mice in which model antigens are experimentally introduced or ectopically expressed (55). While this approach has been instrumental to our understanding of how cognate antigen recognition shapes conventional and regulatory T cell homeostasis and function, the supra-physiological levels of antigen and high precursor frequencies of antigen-specific T cells typically employed in these systems may misrepresent what occurs for self-antigen recognition at the steady-state.…”