TY - JOUR
T1 - Intrinsic differences in donor CD4 T cell IL-2 production influence severity of parent-into-F1 murine lupus by skewing the immune response either toward help for B cells and a sustained autoantibody response or toward help for CD8 T cells and a downregulatory Th1 response
AU - Soloviova, Kateryna
AU - Puliaiev, Maksym
AU - Haas, Mark
AU - Dalgard, Clifton L.
AU - Schaefer, Brian C.
AU - Via, Charles S.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Using the parent-into-F1 model of induced lupus and (C57BL/6 3 DBA2) F1 mice as hosts, we compared the inherent lupusinducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, nonlupus-prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway that is characterized by IL-2/IFN-γ expression, help for CD8 CTLs, and skewing of dendritic cell (DC) subsets toward CD8a DCs, coupled with reduced CD4 T follicular helper cells and transient B cell help. In contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway that is characterized by poor IL-2/IFN-γ expression, poor help for CD8 CTLs, and skewing of DC subsets toward plasmacytoid DCs, coupled with greater CD4 T follicular helper cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene-expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IkBa, and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and toward help for CTLs may be beneficial.
AB - Using the parent-into-F1 model of induced lupus and (C57BL/6 3 DBA2) F1 mice as hosts, we compared the inherent lupusinducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, nonlupus-prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway that is characterized by IL-2/IFN-γ expression, help for CD8 CTLs, and skewing of dendritic cell (DC) subsets toward CD8a DCs, coupled with reduced CD4 T follicular helper cells and transient B cell help. In contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway that is characterized by poor IL-2/IFN-γ expression, poor help for CD8 CTLs, and skewing of DC subsets toward plasmacytoid DCs, coupled with greater CD4 T follicular helper cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene-expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IkBa, and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and toward help for CTLs may be beneficial.
UR - http://www.scopus.com/inward/record.url?scp=84942455971&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1402782
DO - 10.4049/jimmunol.1402782
M3 - Article
C2 - 26320249
AN - SCOPUS:84942455971
SN - 0022-1767
VL - 195
SP - 2985
EP - 3000
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -