The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

Abstract

The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.Armed with the potential to destroy invading microorganisms and stop aberrant outgrowth of tumor cells, the immune system has extensive built-in mechanisms for preventing attack of healthy self tissues. The first line of such 'self-tolerance' is the elimination of selfreactive T lymphocytes and B lymphocytes during negative selection in the thymus and bone marrow, respectively. However, there has long been a belief that the immune system must have peripheral mechanisms in place to deal with immune cells that 'escape' central tolerance. For almost 40 years, immunologists have postulated the existence of suppressor T cells that police the immune system to avert unwanted immune responses 1-3 . However, that phenomenology was cast into doubt as various labs presented unique, hard-to-reproduce systems, each with complexities and idiosyncrasies that raised credibility issues. This situation was not unlike the early years of cytokine biology, during which dozens of activities were found in sera and cell supernatants without consistent molecular or biochemical 'signatures'. Fortunately, as biochemistry and the molecular biology revolution rescued the field of cytokine biology by identifying genes and biochemical structures tied to the varied biologic activities, the identification of a constellation of cell surface, transcriptional and biochemical markers that uniquely mark 'regulatory' T cells (T reg cells) has made possible a rebirth of the suppressor T cell field over the past decade.The realization that T reg cells have a unique surface expression profile incorporating CD25, CD62L and specific CD45 isoforms 4-6 , together with the identification of the T reg cellspecific transcription factor Foxp3, catapulted T reg cells from a rare CD4 + T cell subset to

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

“…Although multiple molecular events have been proposed to explain Treg suppression of immune cell (particularly ab Teff) functions [13], none is able to account for all aspects of Treg activity, and it is therefore likely that combinations of various mechanisms operate at any given time. .…”

“…CD4 1 CD25 1 ab T cells are well known for their ability to control the activity of several immune cell populations in vitro and in vivo, including effector CD4 1 CD25 À and CD8 1 ab T cells [13], NK [14] and NKT cells [15], B cells [16], DC [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring'' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21].…”

“…Of note, the employment of naïve mice raised in specific pathogenfree housing conditions allowed us to assign these effects to either nTreg or iTreg (see Fig. 2), which would be essentially impossible to do in human volunteers.Although multiple molecular events have been proposed to explain Treg suppression of immune cell (particularly ab Teff) functions [13], none is able to account for all aspects of Treg activity, and it is therefore likely that combinations of various mechanisms operate at any given time. .…”

Human FOXP3 and cancer

“…These FOXP3-dependent modifications of gene expression in Treg are therefore directly linked to their capacity to promote or repress an immune response and involve various mechanisms, such as the FOXP3-dependent CTLA4 overexpression on Treg, which interacts with CD80 and CD86 costimulatory signals on dendritic cells (Tang and Bluestone, 2008;Shevach, 2009). …”

Foxp3‐independent loss of regulatory CD4+T‐cell suppressive capacities induced by self‐deprivation

“…6B). granzyme B [25]. Expression of these molecules was not modified (or augmented) by self-deprivation (Supporting Information Fig.…”