Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells.
IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) alpha subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R-deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A-secreting CD4(+) T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4(+) T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.
Jones
Gareth W
GW
Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, Wales, UK.
McLoughlin
Rachel M
RM
Hammond
Victoria J
VJ
Parker
Clare R
CR
Williams
John D
JD
Malhotra
Raj
R
Scheller
Jürgen
J
Williams
Anwen S
AS
Rose-John
Stefan
S
Topley
Nicholas
N
Jones
Simon A
SA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013203:Staphylococcal Infections / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6