Page 215 - Clinical Immunology_ Principles and Practice ( PDFDrive )
P. 215
CHAPTER 12 T-Cell Activation and Tolerance 195
deprivation can kill proliferating T cells in a B cell lymphoma 4. Rhee I, Veillette A. Protein tyrosine phosphatases in lymphocyte
2–interacting (Bcl2-interacting) mediator (BIM)-dependent activation and autoimmunity. Nat Immunol 2012;13:439–47.
manner. Tregs preferentially express Galectin-1, a β- 5. Notarangelo LD. Immunodeficiency and immune dysregulation
galactoside-binding protein that ligates CD45 and other lym- associated with proximal defects of T cell receptor signaling. Curr Opin
Immunol 2014;31:97–101.
phocyte surface molecules and that may suppress lymphocyte 6. Gomez-Rodriguez J, Kraus ZJ, Schwartzberg PL. Tec family kinases Itk
activation through induction of cell cycle arrest. Treg surface and Rlk / Txk in T lymphocytes: cross-regulation of cytokine production
proteins that work to effectively decrease efficiency of antigen and T cell fates. FEBS J 2011;278:1980–9.
presentation by DCs include CTLA-4, which interferes with 7. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev
CD28-dependent T-cell costimulation; LAG3, which binds to Immunol 2009;27:591–619.
MHC class II molecules and prevents DC maturation; and Nrp1, 8. Hogan PG, Lewis RS, Rao A. Molecular basis of calcium signaling in
which mediates prolonged Treg/DC interactions that may restrict lymphocytes: STIM and ORAI. Annu Rev Immunol 2010;28:491–533.
access of effector T cells to DCs. 9. Krishna S, Zhong XP. Regulation of lipid signaling by diacylglycerol
kinases during T cell development and function. Front Immunol
2013;4:178.
SUMMARY AND FUTURE DIRECTIONS 10. Burbach BJ, Medeiros RB, Mueller KL, et al. T cell receptor signaling to
integrins. Immunol Rev 2007;218:65–81.
11. Jun JE, Rubio I, Roose JP. Regulation of ras exchange factors and cellular
ON THE HORIZON localization of ras activation by lipid messengers in T cells. Front
Immunol 2013;4:239.
• Better understanding of T-cell intracellular signaling pathways will lead 12. So T, Croft M. Regulation of PI-3-Kinase and Akt signaling in T
to improved immunomodulatory therapies lymphocytes and other cells by TNFR family molecules. Front Immunol
• Promising targets for manipulation of T-cell signaling include: 2013;4:139.
• SYK inhibition 13. Stark AK, Sriskantharajah S, Hessel EM, et al. PI3K inhibitors in
• AKT inhibition inflammation, autoimmunity and cancer. Curr Opin Pharmacol
• Tec kinase inhibition in cancer 2015;23:82–91.
• Targets for relief of negative checkpoints on T-cell activation for 14. Shi JH, Sun SC. TCR signaling to NF-kappaB and mTORC1: expanding
immunoenhancement in cancer or infection include: roles of the CARMA1 complex. Mol Immunol 2015;68:546–57.
• LAG3, TIGIT, TIM3, BTLA, VISTA 15. Jordan MS, Singer AL, Koretzky GA. Adaptors as central mediators of
signal transduction in immune cells. Nat Immunol 2003;4:110–16.
16. Balagopalan L, Kortum RL, Coussens NP, et al. The linker for activation
Antigen receptor signaling controls key T-cell developmental of T cells (LAT) signaling hub: from signaling complexes to microclusters.
checkpoints as well as the fate and behavior decisions of mature J Biol Chem 2015;290:26422–9.
T cells. Membrane-proximal TCR signaling depends on tyrosine 17. Simeoni L, Lindquist JA, Smida M, et al. Control of lymphocyte
phosphorylation events that are coupled to “second messenger” development and activation by negative regulatory transmembrane
cascades through adaptor proteins. TCR affinity for ligand is the adapter proteins. Immunol Rev 2008;224:215–28.
major determinant for life-or-death decisions by immature 18. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and
co-inhibition. Nat Rev Immunol 2013;13:227–42.
thymocytes that result in establishment of a broadly self-tolerant 19. Artyomov MN, Lis M, Devadas S, et al. CD4 and CD8 binding to MHC
mature T-cell repertoire. In peripheral T cells, auxiliary signals molecules primarily acts to enhance Lck delivery. Proc Natl Acad Sci USA
from costimulatory molecules, coreceptors, growth factor recep- 2010;107:16916–21.
tors, and metabolic sensors all shape the transcriptional regulation 20. Baumeister SH, Freeman GJ, Dranoff G, et al. Coinhibitory pathways in
programs that govern cell function. T cells proliferate and produce immunotherapy for cancer. Annu Rev Immunol 2016;34:539–73.
cytokines when members of the CD28 or TNFR families of 21. Sharpe AH. Mechanisms of costimulation. Immunol Rev 2009;229:
receptors signal in tandem with the TCR. Immunoreceptor and 5–11.
costimulatory signals are also critical in maintaining immune 22. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor
tolerance through clonal deletion, anergy, and peripheral sup- expression and signal transduction. Immunol Rev 2009;229:12–26.
pression by Tregs. Coinhibitory signals that restrain T-cell 23. Linterman MA, Denton AE, Divekar DP, et al. CD28 expression is
antitumor functions may be antagonized for immunotherapy required after T cell priming for helper T cell responses and protective
immunity to infection. Elife 2014;3. doi:10.7554/eLife.03180.
of cancer. More detailed understanding of T-cell intracellular 24. Zhang R, Huynh A, Whitcher G, et al. An obligate cell-intrinsic function
signaling pathways will lead to more specific, targeted immu- for CD28 in Tregs. J Clin Invest 2013;123:580–93.
nomodulatory therapies. 25. Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and
CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Please check your eBook at https://expertconsult.inkling.com/ Science 2011;332:600–3.
for self-assessment questions. See inside cover for registration 26. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell
details. exhaustion. Nat Rev Immunol 2015;15:486–99.
27. Turnis ME, Andrews LP, Vignali DA. Inhibitory receptors as targets for
cancer immunotherapy. Eur J Immunol 2015;45:1892–905.
REFERENCES 28. Croft M. Control of immunity by the TNFR-related molecule OX40
(CD134). Annu Rev Immunol 2010;28:57–78.
1. Weiss A, Littman DR. Signal transduction by lymphocyte antigen 29. Le Floc’h A, Huse M. Molecular mechanisms and functional implications
receptors. Cell 1994;76:263–74. of polarized actin remodeling at the T cell immunological synapse. Cell
2. Guy CS, Vignali DA. Organization of proximal signal initiation at the Mol Life Sci 2015;72:537–56.
TCR:CD3 complex. Immunol Rev 2009;232:7–21. 30. Yokosuka T, Saito T. Dynamic regulation of T cell costimulation through
3. Stanford SM, Rapini N, Bottini N. Regulation of TCR signalling by TCR-CD28 microclusters. Immunol Rev 2009;229:27–40.
tyrosine phosphatases: from immune homeostasis to autoimmunity. 31. Owen RD. Immunogenetic consequences of vascular anastomoses
Immunology 2012;137:1–19. between bovine twins. Science 1945;102:400–1.

