CD28 signals in the immature immunological synapse.
T cell recognition of peptide-MHC complexes on APCs results in the aggregation of TCRs at a central supramolecular activation complex (c-SMAC) within a mature immunological synapse. T cells require a second "costimulatory" signal for activation, the most important of which, for naive T cells, is from CD28. However the time at which CD28-derived signals are induced relative to c-SMAC formation is not well understood. In this study, we have assessed the kinetics of CD28 localization and function relative to well-established aspects of c-SMAC formation. CD28 accumulates at the immature synapse alongside the TCR and is likewise enriched at the synapse at the onset of the calcium signal. In addition, using CD28 deficient or reconstituted murine cells in a single-cell recording approach shows that CD28 regulates this signal within seconds of a TCR-mediated rise in intracellular calcium levels. Finally, CD28 exerts effects on both the initiation and stabilization of the synapse in parallel with its effects on the downstream proliferation of T cells. Together, the data show that CD28 functions in the immunological synapse before the formation of the c-SMAC.
Andres
Pietro G
PG
Department of Pathology, and Division of Gastroenterology, University of California, San Francisco, CA 93143, USA.
Howland
Kimberly C
KC
Dresnek
Douglas
D
Edmondson
Samuel
S
Abbas
Abul K
AK
Krummel
Matthew F
MF
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017252:CD3 Complex / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D017252:CD3 Complex; D000949:Histocompatibility Antigens Class II; C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin; D002118:Calcium