IL-7 Drives Cytokine Secretion of IL-7Rabright CCR9-Expressing T-Follicular Helper-like Cells: Potential New Axis in Lymphoid Neogenesis in Salivary Glands of Primary Sjogren s Syndrome Patients

S.L.M. Blokland^1,2, M.R. Hillen^1,2, A.A. Kruize¹, A. Kislat³, S. Meller³, B. Homey³, G.M. Smithson⁴, J. Zalevsky⁵, T.R.D.J. Radstake^1,2 and J.A.G. van Roon^1,6, ¹Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Department of Dermatology, University of Düsseldorf, Medical Faculty, Düsseldorf, Germany, ⁴Takeda Pharmaceuticals International, Chicago, IL, ⁵Takeda California, San Diego, CA, ⁶Laboratory for Translational immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Chemokine Receptors, chemokines and interleukins (IL), Sjogren's syndrome, T cells

Session Information

Date: Tuesday, November 10, 2015

Title: Sjögren's Syndrome II: Clinical Discoveries

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

In primary Sjögren’s syndrome (pSS) B cell hyperactivity including autoantibody secretion and lymphoma development are hallmark immunopathological features. Specific lymphoid organization (including germinal centers) is associated with increased risk for development of extraglandular manifestations and lymphoma. Thus better understanding of the cellular and molecular pathways that underlie formation of ectopic lymphoid structures is of pivotal importance. T follicular helper (Tfh) cells, expressing ICOS and cytokines like IL-21 play a critical role in the formation of such structures and in activation of B cells. Recently, a novel subset of CD4+ T cells found to have Tfh-like characteristics was found to be specifically attracted to mucosal sites by CCL25, the ligand for CCR9. Our objective was to investigate the role of CCR9+ T cells and CCL25 in pSS.

Methods:

Levels of CCL25 and 103 other soluble targets were measured in serum and washouts from labial salivary gland (LSG) biopsies by Luminex. CCL25 mRNA in LSG was quantified by qPCR. CCR9-expressing cells were assessed in the LSG by immunohistochemistry. Circulating CCR9-expressing cells were assessed by flow cytometry and cultured to assess functional properties (cytokine production).

Results:

Increased CCL25 was measured in serum of pSS and nSS patients as compared to HC (median pSS, nSS, HC 2.75, 2.61 and 1.99 ng/mL, sicca patients vs HC: p=0.04, nSS vs pSS: ns). CCL25 serum levels in pSS correlated with chemokines involved in formation of ectopic lymphoid structures CXCL13 and CCL19, and proinflammatory cytokines IL-12 and TWEAK. In addition, pSS patients displayed around an increase in CCL25 mRNA levels in LSG (p=0.04) and increased CCL25 protein levels in LSG washouts as compared to nSS patients (median 1.24 vs 0.97 ng/mL, p=0.04). pSS patients showed enhanced numbers of CCR9-expressing cells in the salivary gland (mean pSS 9.2, nSS 3.8 cells/mm2, p=0.006). Interestingly, CCR9+ Th cells from pSS patients express increased levels of PD-1 and ICOS (both p<0.05). In addition, CCR9+ T cells expressed significantly higher levels of IL-7Rα as compared to CXCR5 Tfh precursor cells (p<0.01) and secreted strongly increased levels of IFN-y, IL-10, IL- 17, IL-6, IL-21 but not CXCL13 upon stimulation with IL-7 as compared to CXCR5+ Tfh cells.

Conclusion:

Enhanced expression of CCL25 could significantly contribute to the increased numbers of CCR9+ cells in particular CCR9-expressing Tfh-like cells in labial salivary glands from pSS patients. Considering the increased expression of ICOS and IL-7Rα on CCR9+ Th cells and the capacity of IL-7 to induce pro-inflammatory and Tfh-like cytokine secretion this suggests that the CCL25/CCR9-axis might play a significant role in lymphoid neogenesis and immunopathology of pSS, representing a novel therapeutic target in this disease.

Disclosure: S. L. M. Blokland, Takeda Pharmaceuticals, 9; M. R. Hillen, None; A. A. Kruize, None; A. Kislat, None; S. Meller, None; B. Homey, None; G. M. Smithson, Takeda Pharmaceuticals, 3; J. Zalevsky, Takeda Pharmaceuticals, 3; T. R. D. J. Radstake, Takeda Pharmaceuticals, 9; J. A. G. van Roon, Takeda Pharmaceuticals, 9.

To cite this abstract in AMA style:

Blokland SLM, Hillen MR, Kruize AA, Kislat A, Meller S, Homey B, Smithson GM, Zalevsky J, Radstake TRDJ, van Roon JAG. IL-7 Drives Cytokine Secretion of IL-7Rabright CCR9-Expressing T-Follicular Helper-like Cells: Potential New Axis in Lymphoid Neogenesis in Salivary Glands of Primary Sjogren s Syndrome Patients [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/il-7-drives-cytokine-secretion-of-il-7rabright-ccr9-expressing-t-follicular-helper-like-cells-potential-new-axis-in-lymphoid-neogenesis-in-salivary-glands-of-primary-sjogren-s-syndrome-patients/. Accessed .

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