CD43 regulation of T cell activation is not through steric inhibition of T cell-APC interactions but through an intracellular mechanism.
CD43 is a large heavily glycosylated protein highly expressed on T cells and actively excluded from the immunological synapse through interactions with ezrin-radixin-moesin proteins. Due to its size and charge, it has been proposed that the CD43 ectodomain acts as a physical barrier to T cell-APC interactions. We have addressed this hypothesis by studying the effect of reconstituting CD43 mutants into the hyperproliferative CD43(-/-) T cells. Reintroduction of full-length CD43 reversed the CD43(-/-) T cell hyperproliferation. Interestingly, despite the lack of exclusion from the interaction site, a mutant containing the CD43 ectodomain on a glycosylphosphatidylinositol linkage was ineffective. Additionally, T cell-APC conjugate formation was not affected by this ectodomain-only construct. In contrast, CD43(-/-) T cell hyperproliferation was reversed by an intracellular-only CD43 fused to the small ectodomain of hCD16. Mutation of this intracellular-only CD43 such that it could not move from the T cell-APC contact site had no further affect on proliferation than the moveable CD43 but did dramatically reduce interleukin-2 production. Thus, the exclusion of the CD43 intracellular region from the immunological synapse is required for CD43 regulation of interleukin-2 production, but the presence of the cytoplasmic tail, independent of its location, is sufficient to reverse CD43(-/-) T cell hyperproliferation.
Tong
Jiankun
J
Department of Medicine, The Committee on Immunology and Section of Pulmonary and Critical Care Medicine, University of Chicago, IL 60637, USA.
Allenspach
Eric J
EJ
Takahashi
Stephenie M
SM
Mody
Purvi D
PD
Park
Chan
C
Burkhardt
Janis K
JK
Sperling
Anne I
AI
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D005455:Fluorescent Antibody Technique; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D051917:Leukosialin; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D012795:Sialoglycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D007376:Interleukin-2; D051917:Leukosialin; D012795:Sialoglycoproteins; C497863:Spn protein, mouse