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Abstract Number: 3023

Decreased Intracellular Calcium Flux in Follicular Helper T Cells after T Cell Receptor Stimulation

Abhinav Seth1, Edward I. Herman2, Jason S. Weinstein1, Jin Young Choi3 and Joseph E. Craft4, 1Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT, 2Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 3Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT, 4Dept of Internal Med/Rheum, Yale University School of Medicine, New Haven, CT

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: calcium and signal transduction, Lupus, T cells

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Session Information

Date: Tuesday, November 10, 2015

Title: T cell Biology and Targets in Autoimmune Disease Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Follicular helper T (Tfh) cells are a specialized subset of CD4+ helper T cells that are required for B cell maturation in germinal centers and subsequent antibody formation following infection or immunization with thymus dependent antigens.  Tfh cells have also been implicated in mediating pathogenic autoantibody production in lupus and modulation of their function has been shown to ameliorate end organ disease in murine models of lupus.  Understanding the molecular determinants of Tfh cell function may allow for the development of specifically targeted immunomodulating therapies for lupus and other autoantibody mediated diseases.  In this study, we have systematically characterized the ability of Tfh cells from a variety of physiologic and pathologic settings to flux calcium in response to T cell receptor stimulation.   

Methods:

B6 mice were immunized in bilateral foot pads with a mixture of papain and 4-Hydroxy-3-nitrophenylacetyl conjugated to ovalbumin (NP-OVA).  After 5 days, inguinal and popliteal lymph nodes were harvested and lymphocytes were labeled with fluorophore-conjugated antibodies to allow identification of different T cell subtypes by flow cytometry.  Cells were loaded with the calcium sensitive dyes Fluo4 and FuraRed to allow ratiometric imaging of intracellular calcium.  Cells were stimulated with anti-CD3 antibodies to initiate T cell receptor (TCR) signaling and the intracellular calcium concentration was monitored in naïve T cells, Tfh cells and other effector T cells subtypes.  Similar experiments were conducted using T cells obtained from the spleens of 1) B6 mice infected with the helminth Nippostrongylus brasiliensis, 2) B6 mice acutely infected with lymphocytic choriomeningitis virus or 3) 6 month old lupus-prone, B6.Sle1.Yaa, mice.

Results:

Tfh cells, relative to naïve T cells or to their Th1 or Th2 counterparts, exhibit significantly reduced calcium flux upon TCR stimulation in the context of NP-OVA immunization (2.4-fold reduction, p < 0.0001), helminth infection (3.7-fold reduction, p < 0.0001), viral infection (2.3-fold reduction, p < 0.0001) or autoimmune activation in lupus-prone mice (3.3-fold reduction, p <0.0001).  These findings are not due to generalized defects in signaling as Tfh cells retain the ability to activate MAP kinases following TCR stimulation, suggesting a specific alteration in the ability of Tfh cells to handle calcium.

Conclusion:

Our results demonstrate that Tfh cells, in physiologic or pathogenic settings, have a selective defect in calcium mobilization upon TCR stimulation.  The altered calcium handling profile of Tfh cells likely contributes to the unique molecular program of these specialized cells.  These results have important implications for designing therapeutic strategies to selectively target Tfh cells in autoimmune disease.


Disclosure: A. Seth, None; E. I. Herman, None; J. S. Weinstein, None; J. Y. Choi, None; J. E. Craft, AbbVie, 2.

To cite this abstract in AMA style:

Seth A, Herman EI, Weinstein JS, Choi JY, Craft JE. Decreased Intracellular Calcium Flux in Follicular Helper T Cells after T Cell Receptor Stimulation [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/decreased-intracellular-calcium-flux-in-follicular-helper-t-cells-after-t-cell-receptor-stimulation/. Accessed .
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