IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection.
Previous studies have revealed that a population of innate memory CD8(+) T cells is generated in response to IL-4, first appearing in the thymus and bearing high expression levels of Eomesodermin (Eomes) but not T-bet. However, the antigen specificity and functional properties of these cells is poorly defined. In this study, we show that IL-4 regulates not only the frequency and function of innate memory CD8(+) T cells, but also regulates Eomes expression levels and functional reactivity of naive CD8(+) T cells. Lack of IL-4 responsiveness attenuates the capacity of CD8(+) T cells to mount a robust response to lymphocytic choriomeningitis virus infection, with both quantitative and qualitative effects on effector and memory antigen-specific CD8(+) T cells. Unexpectedly, we found that, although numerically rare, memory phenotype CD8(+) T cells in IL-4Rα-deficient mice exhibited enhanced reactivity after in vitro and in vivo stimulation. Importantly, our data revealed that these effects of IL-4 exposure occur before, not during, infection. Together, these data show that IL-4 influences the entire peripheral CD8(+) T cell pool, influencing expression of T-box transcription factors, functional reactivity, and the capacity to respond to infection. These findings indicate that IL-4, a canonical Th2 cell cytokine, can sometimes promote rather than impair Th1 cell-type immune responses.
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455.
Kristin R
0000-0003-4000-3356
KR
Renkema
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455.
June-Yong
0000-0002-4476-725X
JY
Lee
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455.
You Jeong
YJ
Lee
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455.
Sara E
SE
Hamilton
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455.
Kristin A
0000-0001-9963-5687
KA
Hogquist
Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 james024@umn.edu.
Stephen C
SC
Jameson
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D007156:Immunologic Memory / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D053662:Interleukin-4 Receptor alpha Subunit
D015847:Interleukin-4; D011956:Receptors, Cell Surface; D020825:T-Box Domain Proteins; C491198:Eomes protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit