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OP0258 IL-22 Regulates Lymphoid Stromal Cell Expansion, Development of Germinal Centers and Humoral Response in Mucosal Ectopic Lymphoneogenesis
  1. S. Nayar1,
  2. T. Cloake1,
  3. P. Lane2,
  4. C. Pitzalis3,
  5. M. Coles4,
  6. S. Luther5,
  7. C. Buckley1,
  8. F. Barone1
  1. 1Rheumatology Research Group
  2. 2Immunity and Infection, University of Birmingham, Birmingham
  3. 3Centre for Experimental Medicine and Rheumatology, William Harvey Reasearch Institute, London
  4. 4Centre for Immunology and Infection, University of York, York, United Kingdom
  5. 5Department of Biochemistry, University of Lausanne, Lausanne, Switzerland

Abstract

Background Failure to treat autoimmune diseases with leukocyte-targeted therapies, candidates locally residing stromal cells as possible therapeutic intervention in chronic disease management. Phenotypical changes associated with the acquisition of lymphoid-like features has been described in stroma of chronic disease and cancer. gp38, marker of lymph node stromal cell, has been used to identify and isolate stromal cells that acquire in ectopic organs the capability to support lymphoid chemokines (CKs)/cytokine production and lymphocyte compartmentalization (1).

Objectives Dissect the molecules and mechanisms regulating differentiation of resident stromal towards gp38+lymphoid like phenotype.

Methods We designed an inducible model of ectopic lymphoneogenesis in salivary glands to evaluate the dynamics of stromal cell activation. Salivary glands of C57BL/6 mice wild type and knockout mice (IL-22, IL22R, RAG, LTbR) were cannulated with adenovirus and sacrificed at different time points post cannulation (p.c.). Immunofluorescence, flow cytometry, RT-PCR and ELISA were used to evaluate the dynamic of acquisition of lymphoid features.

Results WT mice stromal cells display early acquisition of lymphoid features, up-regulating gp38 already at 3hours pc. Peak of this activation was observed at day5 with significant increase in the percentage of gp38+ lymphoid like stromal cells (LLSc), this increase is maintained between day8-15 pc. However, full acquisition of lymphoid phenotype, indicated by high levels of lymphoid CKs/cytokine expression was observed by day8-15 pc. This correlates with full maturation of the lymphoid aggregates in terms of T/B cell segregation and FDC formation. Of interest, RAG and LTbR KO mice showed normal degree of stromal cell activation in the early phases (2-5days p.c.) but a dramatic decrease in the percentage of LLSc by day15. However, these KOs exhibited a defect in full lymphoid conversion of stromal cells shown by significant decrease in CKs/cytokine expression and aggregates disorganization, suggesting that the full maturation of stromal cells require lymphocyte-derived signals such as lymphotoxin. Surprisingly in IL-22 and IL-22R KOs lack of gp38 up-regulation at day5 and 8 pc was observed, with significant decrease in LLSc percentage and this defect was attributed to defective LLSc proliferation. This quantitative defect in LLSc translated to severe impairment in local overexpression of the lymphoid CKs/cytokines both at protein and mRNA level. Accordingly, IL-22KO mice showed small, disorganized aggregates, defects in the antiviral response and abrogation of the antinuclear antibody production.

Conclusions Our study provides the first in vivo evidence that IL-22 plays a critical role in aquisition and expansion of lymphoid like stromal cell during inflammation. This first phase is followed by full conversion of the stromal cells to a lymphoid-like phenotype and requires lymphotoxin beta provided lymphocytes. This data support the role of stroma as “malignant soil” in chronic conditions and strongly suggests the need for a dual therapeutic approach aimed to target both leukocyte and stroma to achieve disease control.

References

  1. Peduto et al., J Immunol, 2009.

Disclosure of Interest None Declared

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