T Regulatory Cells

Regulators of the Immune System

Regulatory T cells (Tregs) are critical to the maintenance of immune cell homeostasis as evidenced by the catastrophic consequences of genetic or physical ablation of the Treg population. Specifically, Treg cells maintain order in the immune system by enforcing a dominant negative regulation on other immune cells. Broadly classified into natural or adaptive (induced) Tregs; natural Tregs are CD4+CD25+ T-cells which develop, and emigrate from the thymus to perform their key role in immune homeostasis. Adaptive Tregs are non-regulatory CD4+ T-cells which acquire CD25 (IL-2R alpha) expression outside of the thymus, and are typically induced by inflammation and disease processes, such as autoimmunity and cancer.

Precise understanding of the immunosuppressive mechanism of T regulatory cells remains elusive, although there is increasing evidence that Tregs manifest their function through a myriad of mechanisms that include the secretion of immunosuppressive soluble factors such as IL-9, IL-10 and TGF beta, cell contact mediated regulation via the high affinity TCR and other costimulatory molecules such as CTLA-4, GITR, and cytolytic activity. Understanding the mechanisms by which Treg cells exert their influence is an area of intense research with broad implications for the development of therapeutic strategies for many disease processes including cancer, diabetes, and Immune mediated diseases.

T Regulatory Cell Lineage

Under the influence of TGF beta, adaptive Treg cells mature in peripheral sites, including mucosa-associated lymphoid tissue (MALT), from CD4+ Treg precursors, where they acquire the expression of markers typical of Tregs, including CD25, CTLA4 and GITR / AITR. Upon up-regulation of the transcription factor Foxp3, Treg cells begin their suppressive effect. This includes the secretion of cytokines including IL-10 and TGF beta which may induce cell-cycle arrest or apoptosis in effector T cells, and blocking co-stimulation and maturation of dendritic cells.

T Regulatory Cell Properties
PropertyNatural Treg (nTreg)Induced Treg (iTreg) - Tr1Induced Treg (iTreg) - Th3
Development Thymus Periphery (MALT) Periphery (MALT)
Phenotype CD4+CD25+CD127low CD4+CD25- CD4+CD25+ from CD25- precursors
Other Associated Markers CTLA-4+GITR+Foxp3+ CD45RBlowFoxp3- CD25low-variableCD45RBlowFoxp3+
Suppression Contact-, Granzyme-B dependent, makes TGF beta IL-10 mediated TGF beta mediated
Target Cells APC and Effector T Cells Effector T Cells Unknown
CD28 Involvement

Thymic development and maintenance in periphery

Unnecessary for development or function Unnecessary for development or function
in vivo Role Suppression of autoreactive T cells Mucosal immunity, inflammatory response Mucosal immunity, inflammatory response
in vitro Expansion TCR/CD28 stimulation and IL-2 CD3, IL-10, Retinoic Acid CD3, TGF beta

References

Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S. Int Immunol. 1998 Dec;10(12):1969-80.

Regulatory T cells in autoimmmunity. Shevach EM. Annu Rev Immunol. 2000;18:423-49. Review.

Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Curotto de Lafaille MA, Lafaille JJ. Immunity. 2009 May;30(5):626-35. Review.