Lokeshchandra Kalekar

University of Minnesota

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Marc K. Jenkins

University of Minnesota Medical Center

Daniel L. Mueller

University of Minnesota Medical Center

Shirdi E. Schmiel

Arena Pharmaceuticals (United States)

Jared H. Rowe

Boston Children's Hospital

Sing Sing Way

Cincinnati Children's Hospital Medical Center

James M. Ertelt

R&D Systems (United States)

Tanner M. Johanns

Washington University in St. Louis

Calvin Law

Northwestern University

Jessica Yang

Garvan Institute of Medical Research

Hope O’Donnell

Adaptive Biotechnologies (United States)

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University of Minnesota

University of Minnesota Medical Center

Cincinnati Children's Hospital Medical Center

Office of Infectious Diseases

Twin Cities Orthopedics

Pediatrics and Genetics

University of Cincinnati

Perinatal Institute

Children’s Institute

Institute of Immunology

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Early eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection

Microbes and Infection (2010)

Tanner M. Johanns Calvin Law Lokeshchandra Kalekar Hope O’Donnell James M. Ertelt

Salmonella infection

Adoptive Cell Transfer

10.1016/j.micinf.2010.11.004

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Polyclonal anergic CD4 T cells give rise to pathogenic TH1 and suppressive regulatory T cells during lymphopenia. (P1024)

The Journal of Immunology (2013)

Lokeshchandra Kalekar Marc K. Jenkins Daniel L. Mueller

Abstract Anergy is defined as a state of hyporesponsiveness during which T cells fail to respond to their cognate antigen. Studying anergy using non-transgenic animals has been difficult due to lack of distinguishing markers for anergic cells. We identified CD73 and Folate Receptor 4 (FR4) to be highly expressed in anergic cells from transgenic animals following gene array analysis. Here, we show that CD44hi polyclonal CD4 T cells from non-transgenic animals expressing CD73 and FR4 are hyporesponsive following in vitro stimulation. Anergic T cells with specificity for a known self-antigen also express these markers. Adoptive transfer of these cells into lymphopenic animals leads to reversal of their anergic phenotype and differentiation to Tbet+ TH1 T cells and Foxp3+ regulatory T cells. Selective ablation of Treg cells, which arise following adoptive transfer, leads to accelerated weight-loss and lymphoproliferative disease in mice receiving these anergic cells. Our data suggest that anergy is not a stable state and anergic cells can reverse to diverse functional phenotypes. This finding has important implications for cancers, where anergy reversal and helper T cell differentiation in tumor infiltrating lymphocytes would be a favorable outcome, as well as for autoimmunity, where anergy reversal associated with Treg development could be beneficial.

Adoptive Cell Transfer

Clonal anergy

10.4049/jimmunol.190.supp.65.13

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Adenosine 2A Receptor Promotes Tolerance by Reducing Germinal Center Follicular Helper T cells and Pathogenic Class-Switched B cells

The Journal of Immunology (2016)

Shirdi E. Schmiel Jessica Yang Lokeshchandra Kalekar Marc K. Jenkins Daniel L. Mueller

Abstract Enhanced production of high affinity class-switched autoantibodies contributes to pathological symptoms of autoimmune diseases. Full penetrance of autoantibody production appears to rely on help from germinal center follicular helper T cells (GC TFH cells). GC TFH cells promote the survival, differentiation, isotype class switch, and affinity maturation of B cells. Previous studies have reported that activation of Adenosine receptor 2a (A2aR) downstream signaling negatively regulates adaptive immune responses by limiting the function of effector T cells. Recent work from our lab has demonstrated that the A2aR-specific agonist blocks autoimmune arthritis that is mediated by GPI-specific KRN CD4 T cells. A2aR agonist caused a reduction of GC TFH cells that respond to autoantigen. Consistent with this, GPI-specific humoral immune responses were also reduced in A2aR agonist treated mice. To establish if the effect of A2aR agonist treatment on GC TFH differentiation was T cell intrinsic, CD4-Cre A2aR-floxed B6 mice were immunized with a protein complex containing a CD4 T cell antigen (2W1S peptide) and B cell antigen (PE). Polyclonal 2W1S/I-Ab-specific CD4 T cells and PE-specific B cells were then monitored in the presence or absence of T cell-specific A2a receptors. Our data show that in the absence of T cell-specific A2a receptors, agonist treatment fails to influence GC TFH cell differentiation. Therefore, A2aR downstream signaling can be stimulated within autoreactive CD4 T cells during their encounter with self antigen, and can serve to limit the differentiation of dangerous GC TFH cell effectors. Ongoing experiments are working to identify the T cell-intrinsic mechanism by which A2aR signaling inhibits GC TFH cell generation.

10.4049/jimmunol.196.supp.210.5

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