T Cell Activation. Costimulation, Inhibition, and the Immunologic Synapse. Immunology’s “Dirty Little Secret”. Early experiments demonstrated that antigen-derived (i.e. TCR-mediated) signals alone are insufficient to initiate an immune response
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Costimulation, Inhibition, and the Immunologic Synapse
Early experiments demonstrated that antigen-derived (i.e. TCR-mediated) signals alone are insufficient to initiate an immune response
A second substance - an “adjuvant” - is required to prevent the induction of tolerance
In vitro, triggering the TCR alone also leads to a tolerant state (known as “anergy”)
“Two-Signal Hypothesis”: Activation of a naïve T cell requires signals from both the TCR (antigen-specific) and a second, co-stimulatory receptor (antigen-independent)
Adjuvants work in part by inducing antigen presenting cells to express ligands for co-stimulatory receptors
Yet another member of the immunoglobulin superfamily (single Ig-V domain)
Expressed on the surface of almost all T cells (100% of mouse T cells, ~80% of human T cells) as a disulfide-linked dimer
Binds to B7-1 (CD80) and B7-2 (CD86) expressed on antigen presenting cells
Cytoplasmic tail has binding motifs for several signaling molecules (PI3K, Grb2, Itk), but no ITAM. It is still unclear what signals CD28 contributes to T cell activation
Signaling by CD28 alone does not stimulate T cells, and only activates PI3K
CTLA-4 is another CD28-related receptor, and binds both B7-1 and B7-2 - avidity is at least 20x as high as CD28
CTLA-4 expression on the surface is undetectable in resting T cells, but is rapidly increased after TCR + CD28 signaling
Unlike CD28, CTLA-4 is inhibitory, and blocks T cell proliferation and IL-2 production - combination of competing B7 molecules away from CD28 and bona fide inhibitory signals (possibly phosphatases, but still not well defined)
Fig. 8.12 T-cell activation through the T-cell receptor and CD28 leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules.
Fig. 8.29 The polarization of T cells during specific antigen recognition
Lipid rafts - also called GEMs (glycolipid enriched microdomains) and DIGs (detergent-insoluble glycolipid-rich domains) - are plasma membrane microdomains
Enriched in cholesterol, glycolipids, and sphingolipids (i.e. lipids that are not glycerol-based), making them more rigid than the surrounding membrane
Some membrane proteins are segregated - selectively enriched or depleted in rafts. Many key signaling molecules (esp. src-family kinases) are constitutively localized to lipid rafts.
Dynamic structures - small rafts can condense to form larger rafts
During T cell activation, TCR, CD28, and many adhesion molecules are recruited into lipid rafts, where they can interact with signaling molecules
The combination of cytoskeletal rearrangement and lipid raft redistribution leads to the formation of a Supramolecular Activation Complex (SMAC) - a highly ordered arrangement of receptors, adhesion molecules, and signaling molecules
Regulatory T Cells
Abbas Chapters 10, 13
1) TH1 - inflammatory response
2) TH2 - anti-inflammatory, B cell response
3) Treg - inhibit immune responses
The main function of CD8+ cells is to differentiate into CTL, which kill pathogen-infected cells
Lesion size (mm)
BALB/c + IL-12
1) Activation-induced cell death (Fas/FasL)
2) “Veto” cells (CD8+; TRAIL/TRAIL-R)
1) TCR signal w/o costimulation?
2) TCR signal + CTLA-4?