Requirement of CTLA-4 counter receptors for IL-4 but not IL-10 elevations during a primary systemic in vivo immune response.
The CD28/CTLA-4 costimulatory signal is required for TCR-mediated T cell activation resulting in increased IL-2 production in vitro, but its role in IL-4 production is unclear and few studies have examined the function of CTLA-4/CD28 in the in vivo immune response. We have examined the in vivo effects of blocking the interaction of B7 with its ligands, CTLA-4 and CD28, in an IL-4 dominant in vivo immune response to goat anti-mouse IgD. This response is characterized by elevations in serum Igs preceded by elevations in IL-2 and the Th2 cytokines: IL-4, IL-9, and IL-10. The fusion protein CTLA4-Ig administered during the in vivo immune response to goat anti-mouse IgD caused an inhibition in elevations of IL-2, IL-4, and IL-9 gene expression at both day 3 and day 6 after immunization. In contrast, IL-10 cytokine gene expression as late as day 6 after immunization was not decreased. Cell sorting analysis demonstrated that TCR-alpha beta +, CD4+ T cells were the primary source of the elevated IL-10, suggesting that T cell activation leading to IL-10 gene expression may not require CTLA-4 ligand interactions. Similarly CTLA4-Ig completely blocked elevations in the number of IL-4- but not IL-10-secreting cells, as measured by ELISPOT, in both unsorted splenic cells and sorted CD4+, TCR-alpha beta+ T cells. In situ staining of spleen sections also showed inhibition of IL-4-producing cells. These results suggest that, with the notable exception of IL-10, interaction, of B7 with its ligands is required for elevated Th2 cytokine gene expression and secretion during a primary systemic IL-4-dominant response.
Lu
P
P
Department of Microbiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Zhou
X D
XD
Chen
S J
SJ
Moorman
M
M
Schoneveld
A
A
Morris
S
S
Finkelman
F D
FD
Linsley
P
P
Claassen
E
E
Gause
W C
WC
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007109:Immunity / Q000276:immunology*; D018796:Immunoconjugates; D007072:Immunoglobulin D / Q000276:immunology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D018418:Th2 Cells / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007072:Immunoglobulin D; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D000069594:Abatacept