565 - IL-21R Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRLlpr Mice

Sunday, November 6, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Andrew L. Rankin1, Tatyana Andreyeva1, Yijun Carrier2, Mary Collins3, Cheryl L. Nickerson-Nutter3, Deborah Young2 and Kyri Dunussi-Joannopoulos3, 1Pfizer, Inc., Cambridge, MA, 2Colleague, Cambridge, MA, 3Pfizer, Cambridge, MA
Presentation Number: 565

Background/Purpose: IL-21 is a pleiotropic cytokine that can influence the activation and proliferation of both B and T cells.  We previously showed that the development of lupus-like disease manifestations in MRLlpr mice could be prevented by blocking IL-21 pharmacologically.  We generated IL-21R deficient MRLlpr mice to examine the impact of loss of IL-21R signaling on the systemic lymphocyte activation and accumulation observed in MRLlpr mice.

Method: C57Bl/6.IL-21R-/- mice were backcrossed with MRLlpr mice to generate MRLlpr.IL-21R-/- mice.  Disease development in MRLlpr.IL-21R-/- mice was monitored in a time-course study that included assessment of proteinuria (Albustix, Bayer), histologic examination of renal pathology and gross evaluation of skin lesions.  B and CD4+ T cell activation status was examined using standard flow cytometric based methods.

Result: MRLlpr.IL-21R-/- mice exhibited significantly decreased proteinuria, lymphadenopathy and reduced severity of cutaneous lesions and renal inflammatory infiltrates. Splenomegaly was reduced in MRLlpr.IL-21R-/- and resulted from a profound reduction in CD4+ T cells, B cells and DN T cells.  The vast majority of CD4+ T cells in MRLlpr mice bore an activated cell surface phenotype (CD44hi CD62lo), which was significantly reduced in MRLlpr.IL-21R-/- mice.  Significantly reduced titers of anti-dsDNA antibodes were present in MRLlpr.IL-21R-/- mice and correlated with a dramatic  reduction in numbers of splenic germinal center B cells and plasma cells.  In addition, both T follicular help and T extrafollicular helper cells, which are key promoters of antibody responses, were significantly reduced in MRLlpr.IL-21R-/- mice.

Conclusion: IL-21R is required for the development of inflammatory lesions in both the kidney and skin of MRLlpr mice.  Moreover, the systemic lymphoaccumulation observed in MRLlpr mice is dependent on signals delivered via IL-21R.  Our data demonstrate that multiple populations of activated B and T lymphocytes depend on IL-21R for their accumulation.  The profound dampening of lymphocyte effector activation in the absence of IL-21R signaling suggests that blockade of the IL-21 pathway may be a promising therapy B and T cell mediated autoimmune diseases such as SLE.

Keywords: activation, cytokines, interleukins, lupus nephritis and mouse model

Disclosure: A. L. Rankin, Pfizer Inc, 3 ; T. Andreyeva, Pfizer Inc, 3 ; Y. Carrier, Pfizer Inc, 3 ; M. Collins, Pfizer Inc, 3 ; C. L. Nickerson-Nutter, Pfizer Inc, 3 ; D. Young, Pfizer Inc, 3 ; K. Dunussi-Joannopoulos, Pfizer Inc, 3 .