IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice.
MRL/MpJ-Fas(lpr/lpr)/J (MRL(lpr)) mice develop lupus-like disease manifestations in an IL-21-dependent manner. IL-21 is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets. Notably, autoreactive CD4(+) T and B cells spontaneously accumulate in MRL(lpr) mice and mediate disease pathogenesis. We sought to identify the particular lymphocyte effector subsets regulated by IL-21 in the context of systemic autoimmunity and, thus, generated MRL(lpr) mice deficient in IL-21R (MRL(lpr).IL-21R(-/-)). Lymphadenopathy and splenomegaly, which are characteristic traits of the MRL(lpr) model were significantly reduced in the absence of IL-21R, suggesting that immune activation was likewise decreased. Indeed, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R-deficient MRL(lpr) mice. Correspondingly, we observed a significant reduction in autoantibody titers. Activated CD4(+) CD44(+) CD62L(lo) T cells also failed to accumulate, and CD4(+) Th cell differentiation was impaired, as evidenced by a significant reduction in CD4(+) T cells that produced the pronephritogenic cytokine IFN-γ. T extrafollicular helper cells are a recently described subset of activated CD4(+) T cells that function as the primary inducers of autoantibody production in MRL(lpr) mice. Importantly, we demonstrated that T extrafollicular helper cells are dependent on IL-21R for their generation. Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL(lpr) mice.
Inflammation and Immunology, Pfizer Research, Cambridge, MA 02140, USA. Andrew.Rankin@pfizer.com
Andrew L
AL
Rankin
Heath
H
Guay
Deborah
D
Herber
Sarah A
SA
Bertino
Tatyana A
TA
Duzanski
Yijun
Y
Carrier
Sean
S
Keegan
Mayra
M
Senices
Nancy
N
Stedman
Mark
M
Ryan
Laird
L
Bloom
Quintus
Q
Medley
Mary
M
Collins
Cheryl
C
Nickerson-Nutter
Joe
J
Craft
Deborah
D
Young
Kyri
K
Dunussi-Joannopoulos
D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053655:Receptors, Interleukin-21 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000098546:Interleukin-21
D001323:Autoantibodies; D007378:Interleukins; D053655:Receptors, Interleukin-21; D007371:Interferon-gamma; D000098546:Interleukin-21