Spontaneous Autoimmunity in the Absence of IL-2 Is Driven by Uncontrolled Dendritic Cells

Abstract

BALB/c IL-2–deficient (IL-2–KO) mice develop systemic autoimmunity, dying within 3 to 5 wk from complications of autoimmune hemolytic anemia. Disease in these mice is Th1 mediated, and IFN-γ production is required for early autoimmunity. In this study, we show that dendritic cells (DCs) are required for optimal IFN-γ production by T cells in the IL-2–KO mouse. Disease is marked by DC accumulation, activation, and elevated production of Th1-inducing cytokines. IL-2–KO DCs induce heightened proliferation and cytokine production by naive T cells compared with wild-type DCs. The depletion of either conventional or plasmacytoid DCs significantly prolongs the survival of IL-2–KO mice, demonstrating that DCs contribute to the progression of autoimmunity. Elimination of Th1-inducing cytokine signals (type 1 IFN and IL-12) reduces RBC-specific Ab production and augments survival, indicating that cytokines derived from both plasmacytoid DCs and conventional DCs contribute to disease severity. DC activation likely precedes T cell activation because DCs are functionally activated even in an environment lacking overt T cell activation. These data indicate that both conventional and plasmacytoid DCs are critical regulators in the development of this systemic Ab-mediated autoimmune disease, in large part through the production of IL-12 and type 1 IFNs.

Spontaneous Proliferation of CD4+ T Cells in RAG-Deficient Hosts Promotes Antigen-Independent but IL-2-Dependent Strong Proliferative Response of Naïve CD8+ T Cells

“…Although IL-2 has not been considered as a modulatory factor for DCs in this study, the enhanced DC expression of co-stimulatory molecules observed with CD4 + T cell transfer into RAG −/− hosts did not seem to require the activity of IL-2—presumably produced from CD4 + T cells transferred—on DCs with mainly two reasons: First, the enhancement of CD80 and CD86 expression on DCs in RAG −/− mice was not detected with in vivo administration of IL-2 delivered as a form of IL-2 and anti-IL-2 immune complexes ( 19 ), for which we also confirmed in our study (data not shown). Second, similar to the results observed with CD4 + T cell transfer into RAG −/− hosts, the enhanced expression of DC costimulatory molecules has also been reported in mice lacking IL-2 or its receptors (CD25 and CD122), which is known to be accompanied by spontaneous activation of conventional CD4 + CD25 − T cells resulting from the lack of Treg suppression in these mice ( 48 ). Hence, although we favor the view that IL-2 is dispensable for inducing the enhanced DC expression of co-stimulatory molecules, the additional experiments—e.g., using adoptive transfer with CD25- or CD122-deficient OT-I cells into RAG −/− hosts—will be necessary to provide strong evidence for a direct stimulatory role of IL-2 on CD8 + T cells.…”

Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2–Deficient Mice

“…To analyze the role of Tfh and Tfr cells in the IL-2 KO, we obtained IL-2 KO mice on the C57BL/6 (B6) background because this strain was genetically compatible with most conditional KO strains that are also on the B6 background. We found that IL-2 KO mice on the B6 background in our facility were healthier than reported for IL-2 KO mice on the BALB/c background (38,39,43). In our colony, most B6 IL-2 KO mice live longer than 5 wk and have a lifespan more similar to what was seen with IL-2 KO mice on the mixed 129-O1a 3 C57BL/6 background (37,38).…”

CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease

“…Cardiac punctures or eye bleeds were performed immediately following cervical dislocation, and blood collected in heparinized tubes (28). Complete blood counts were evaluated within 24 hours on a Hemavet 950 Veterinary Hematology System.…”