IL-2 Receptor Signaling Is Essential for the Development of Klrg1+ Terminally Differentiated T Regulatory Cells

Thymic-derived natural T regulatory cells (Tregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs has been shown to express Klrg1, but it remains unclear as to what extent Klrg1 defines a unique Treg subset. In this study, we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1− Tregs. This subset is a recent Ag-responsive and highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving Ag-activated conventional T lymphocytes also operates for Tregs.

[1]  Jonathan S. Paw,et al.  Response to self antigen imprints regulatory memory in tissues , 2011, Nature.

[2]  G. Smyth,et al.  The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells , 2011, Nature Immunology.

[3]  T. Malek,et al.  Interleukin-2 receptor signaling: at the interface between tolerance and immunity. , 2010, Immunity.

[4]  Diana M. Mitchell,et al.  Distinct Roles for IL-2 and IL-15 in the Differentiation and Survival of CD8+ Effector and Memory T Cells , 2010, The Journal of Immunology.

[5]  C. Benoist,et al.  Genomic definition of multiple ex vivo regulatory T cell subphenotypes , 2010, Proceedings of the National Academy of Sciences.

[6]  W. Haining,et al.  Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. , 2010, Immunity.

[7]  J. Sprent,et al.  IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25 , 2010, Proceedings of the National Academy of Sciences.

[8]  L. Lefrançois,et al.  CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses , 2009, Proceedings of the National Academy of Sciences.

[9]  A. Rudensky,et al.  CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner , 2009, Science.

[10]  L. Bradley.  Faculty Opinions recommendation of The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. , 2009 .

[11]  D. Littman,et al.  Plasticity of CD4+ T cell lineage differentiation. , 2009, Immunity.

[12]  R. Jessberger,et al.  Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. , 2009, Immunity.

[13]  F. Powrie,et al.  Regulatory lymphocytes and intestinal inflammation. , 2009, Annual review of immunology.

[14]  A. Keegan.  Faculty Opinions recommendation of Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. , 2009 .

[15]  Linjiang Zhu,et al.  A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. , 2009, Immunity.

[16]  B. Malissen,et al.  Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity , 2009, Proceedings of the National Academy of Sciences.

[17]  E. Podack,et al.  Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation , 2008, The Journal of experimental medicine.

[18]  C. Hsieh,et al.  A two-step process for thymic regulatory T cell development. , 2008, Immunity.

[19]  M. Farrar,et al.  Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. , 2008, Immunity.

[20]  T. Hanke,et al.  Characterization of mouse CD4 T cell subsets defined by expression of KLRG1 , 2007, European journal of immunology.

[21]  E. Wherry,et al.  Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. , 2007, Immunity.

[22]  Nikhil S. Joshi,et al.  Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. , 2007, Immunity.

[23]  E. Shevach,et al.  Distinct Subsets of FoxP3 Regulatory T Cells Participate in the Control of Immune Responses , 2007 .

[24]  K. Fairfax,et al.  NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation1 , 2007, The Journal of Immunology.

[25]  E. Shevach,et al.  Cutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells , 2007, The Journal of Immunology.

[26]  Vincent C. Manganiello,et al.  Foxp3-dependent programme of regulatory T-cell differentiation , 2007, Nature.

[27]  S. Zheng,et al.  IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells1 , 2007, The Journal of Immunology.

[28]  Y. Wan,et al.  Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression , 2007, Nature.

[29]  W. Haining,et al.  Resolution of a chronic viral infection after interleukin-10 receptor blockade , 2006, The Journal of experimental medicine.

[30]  J. Sprent,et al.  Selective Stimulation of T Cell Subsets with Antibody-Cytokine Immune Complexes , 2006, Science.

[31]  S. Nutt,et al.  Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance , 2006, Nature Immunology.

[32]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[33]  S. Rowland-Jones,et al.  Increased Expression of the NK Cell Receptor KLRG1 by Virus-Specific CD8 T Cells during Persistent Antigen Stimulation , 2005, Journal of Virology.

[34]  A. Kourtis,et al.  Expression of Killer Cell Lectin-Like Receptor G1 on Antigen-Specific Human CD8+ T Lymphocytes during Active, Latent, and Resolved Infection and its Relation with CD57 , 2005, The Journal of Immunology.

[35]  Y. Belkaid,et al.  A Role for CD103 in the Retention of CD4+CD25+ Treg and Control of Leishmania major Infection1 , 2005, The Journal of Immunology.

[36]  M. Kleinewietfeld,et al.  CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. , 2005, Blood.

[37]  T. Malek,et al.  Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period , 2005, The Journal of experimental medicine.

[38]  Shimon Sakaguchi,et al.  Homeostatic maintenance of natural Foxp3 + CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization , 2005, The Journal of experimental medicine.

[39]  A. Rudensky,et al.  Regulatory T cell lineage specification by the forkhead transcription factor foxp3. , 2005, Immunity.

[40]  J. Buer,et al.  Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells , 2004, The Journal of experimental medicine.

[41]  B. Rocha,et al.  A unique subpopulation of CD4+ regulatory T cells controls wasting disease, IL‐10 secretion and T cell homeostasis , 2003, European journal of immunology.

[42]  D. Voehringer,et al.  Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). , 2002, Blood.

[43]  T. Malek,et al.  CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. , 2002, Immunity.

[44]  D. Voehringer,et al.  Viral Infections Induce Abundant Numbers of Senescent CD8 T Cells1 , 2001, The Journal of Immunology.

[45]  T. Malek,et al.  Normal Lymphoid Homeostasis and Lack of Lethal Autoimmunity in Mice Containing Mature T Cells with Severely Impaired IL-2 Receptors1 , 2000, The Journal of Immunology.

[46]  Ethan M. Shevach,et al.  Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigen Nonspecific , 2000, The Journal of Immunology.

[47]  F. Otsuka,et al.  Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. , 1999, Journal of immunology.

[48]  L. Lefrançois,et al.  Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency: parameters in small and large intestine. , 1997, Journal of immunology.

[49]  J. Ashwell,et al.  Interleukin 2 upregulates expression of its receptor on a T cell clone , 1985, The Journal of experimental medicine.

[50]  Shimon Sakaguchi,et al.  Regulatory T cells exert checks and balances on self tolerance and autoimmunity , 2010, Nature Immunology.