1. T-cell activation through the antigen receptor
T-cell activation through the antigen receptor. Part 2: Role of signaling cascades in T-cell differentiation, anergy, immune senescence, and development of immunotherapy 
Andre E. Nel, MD, Ndaisha Slaughter, BS 
Journal of Allergy and Clinical Immunology 
Volume 109, Issue 6, Pages (June 2002)
DOI: /mai
Copyright © 2002 Mosby, Inc. Terms and Conditions

2. Fig. 1
Schematic to explain possible mechanisms by which multiple ITAMs regulate TCR signaling specificity. The TCR signaling apparatus is depicted as a ζ-chain homodimer. A, This model proposes that the stoichiometry of ITAM phosphorylation and TCR signaling potency are directly related. TCR signaling potency refers to both the number and quality of signals, which are induced as explained in Table I.. These outcomes are directly related to the avidity of the TCR for its peptide/MHC ligand. B, In this model individual ITAMs recruit distinct activation complexes that couple the TCR to different downstream signaling pathways. The stoichiometry of ITAM phosphorylation, as determined by the avidity of the TCR-ligand interactions, specifies the type of activation complexes that are recruited to the TCR. This panel depicts 2 putative activation complexes, A and B , that associate with monophosphorylated and biphosphorylated ITAMs, respectively. C, This model proposes that ITAMs might play a negative regulatory role on the basis of the ability of monophosphorylated ITAMs to bind inhibitory complexes (I) that interfere with TCR signal transduction. This inhibition might be overcome in the presence of a ligand that interacts with sufficient avidity with the TCR. Adapted from Love and Shores.14
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions

3. Fig. 2
Schematic to explain the role of the CD28 receptor in delivering signal 2. Interference in CD28 binding to CD80 or CD86 by the blocking ligand CTLA-4Ig results in delivery of signal 1 (TCR) only. This leads to interference in IL-2 production in naive T cells, which might result in anergy or alternative biologic outcomes.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions

4. Fig. 3
Schematic to explain changes in TCR signal transduction in anergic T cells, including the role of the CTLA-4 receptor in inducing the anergic state. These changes include both a subtraction and reduction of signaling required for AP-1-dependent activation of the IL-2 promoter, as well as increased signaling by Fyn kinase and the small GTP-binding protein Rap-1. In addition, anergic T cells maintain PLC-γ1 phosphorylation and ability to generate [Ca2+]i flux. There is also an increase in intracellular cAMP levels, which might be related to increased Rap-1 activity. This increase in cAMP might result in increased expression of the cell-cycle inhibitor p27kip1, a purported anergy factor that is responsible for maintenance of a nonresponsive state during TCR occupancy. Hypothetically, p27kip1 and other anergy factors might be diluted or suppressed by exogenous IL-2 in the culture medium, explaining why this cytokine might induce a recovery from the anergic state. Because T cells must transgress through the cell cycle (in addition to IL-2 production) to avert anergy, it has been proposed that there are 2 distinct states of nonresponsiveness (Table II).41 Additional anergy factors, which might be involved in negative regulation of the IL-2 promoter, are pCREM and Nil-2a (not shown). The binding sites for CREM and Nil-2a in the IL-2 promoter are shown in Fig 6 in part 1 of this review.1a, Change in activity rather than protein abundance.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions

5. Fig. 4
Schematic to explain how differences in TCR signal transduction on the basis of the potency of the stimulus or the type of dendritic cell (DC) might determine TH1 and TH2 differentiation. A, A strong stimulus will lead to a high stoichiometry of ITAM phosphorylation, with subsequent generation of sustained [Ca2+]i flux, JNK, and NF-κB activation (A) . Under these conditions, a range of transcription factors is introduced in the nucleus, which, in the presence of T-bet and STAT4, will favor the activation of TH1 genes. B, Weaker stimuli or activation by type II DCs induces a limited stoichiometry of ITAM phosphorylation, which results in transient [Ca2+]i flux and a modified panel of transcription factors that favor activation of the IL-4 promoter. In addition to the role of GATA-3, c-Maf, STAT6, and NIP45 in this event, the relative ratio of nuclear NFATc versus NFATp/NFAT4 might be an important determining factor. The JNK cascade, as well as the pattern of oscillatory Ca2+ waves, might help to determine the NFAT ratio.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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6. Fig. 5
Schematic to explain altered TCR signal transduction during immune senescence. These changes include decreased activity of several afferent TCR signaling components, notably a decrease in the stoichiometry of ITAM phosphorylation and PTK activity and decreased activation of MAP kinase cascades. This decrease might be due to a broad decline in TCR signaling components or might be the result of altered compartmentalization of signaling components at the TCR synapse. Possible mechanisms to explain these changes in signaling assembly at the TCR synapse include decreased expression and function of the CD28 receptor, altered lipid raft trafficking, change in lipid raft composition, and cytoskeletal assembly. Ultimately, these changes lead to decreased NFAT and AP-1 transcription activity in the nucleus, with a failure in IL-2 production.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions