Page 142 - Clinical Immunology_ Principles and Practice ( PDFDrive )

124 ParT ONE Principles of Immune Response

4. Yang Q, Jeremiah Bell J, Bhandoola A. T-cell lineage determination.
Factors That Dictate CD4 Versus CD8 Commitment Immunol Rev 2010;238:12–22.
Extensive research is being performed to understand the mecha- 5. Ciofani M, Zuniga-Pflucker JC. Determining γδ versus αβT cell
nisms and factors that dictate the CD4/CD8 decision. There are development. Nat Rev Immunol 2010;10:657–63.
known transcription factors that facilitate this process and are 6. Cedar H, Bergman Y. Epigenetics of haematopoietic cell development.
Nat Rev Immunol 2011;11:478–88.
necessary for the differentiation of functional CD4 and CD8 T 7. Shah DK, Zuniga-Pflucker JC. An overview of the intrathymic intricacies
7
cells. Two transcription factors identified as being key to enforcing of T cell development. J Immunol 2014;192:4017–23.
the CD4 and CD8 T-cell lineages are T-helper–inducing POZ- 8. Taghon T, Rothenberg EV. Molecular mechanisms that control mouse and
Kruppel factor (ThPOK) and Runt-related transcription factor human TCR-αβ and TCR-γδ T cell development. Semin Immunopathol
3 (Runx3), respectively. These molecules function to counter- 2008;30:383–98.
regulate each other. ThPOK promotes CD4 T-cell commitment 9. Yui MA, Rothenberg EV. Developmental gene networks: a triathlon on
and silences CD8 T-cell development, in part by repressing the course to T cell identity. Nat Rev Immunol 2014;14:529–45.
expression of Runx3. 16,32-34 Conversely, Runx3 is essential for 10. Pui JC, Allman D, Xu L, et al. Notch1 expression in early lymphopoiesis
35
CD8 T-cell generation and silences CD4 expression in these cells. influences B versus T lineage determination. Immunity 1999;11:
299–308.
Importantly, these two transcription factors are necessary, but 11. Yashiro-Ohtani Y, Ohtani T, Pear WS. Notch regulation of early
not sufficient, to induce CD4 and CD8 SP cells, and other factors, thymocyte development. Semin Immunol 2010;22:261–9.
including GATA-3, are critical in this decision. 16 12. Holmes R, Zuniga-Pflucker JC. The OP9-DL1 system: generation of
Migration of Thymocytes Into the Periphery T-lymphocytes from embryonic or hematopoietic stem cells in vitro. Cold
Spring Harb Protoc 2009;2009:pdb prot5156.
Upon maturation, specific proteins facilitate the migration of 13. Radtke F, Wilson A, Stark G, et al. Deficient T cell fate specification
CD4 and CD8 SP T cells from the thymus. One molecule in mice with an induced inactivation of Notch1. Immunity
responsible for certain aspects of the thymic egress process is 1999;10:547–58.
36
the transcription factor Kruppel-like factor 2 (Klf2). Klf2 is 14. Weber BN, Chi AW, Chavez A, et al. A critical role for TCF-1 in T-lineage
increased after positive and negative selection in SP cells and specification and differentiation. Nature 2011;476:63–8.
drives the expression of sphingosine 1 phosphate receptor 1 15. Germar K, Dose M, Konstantinou T, et al. T-cell factor 1 is a gatekeeper
for T-cell specification in response to Notch signaling. Proc Natl Acad Sci
(S1P1) and L-selectin. Upregulation of S1P1 on the maturing USA 2011;108:20060–5.
T cells is necessary for migration from the thymus, as mice 16. Wang L, Wildt KF, Zhu J, et al. Distinct functions for the transcription
deficient in S1P1 have significantly reduced numbers of circulating factors GATA-3 and ThPOK during intrathymic differentiation of
37
peripheral T cells because the cells are unable to exit the thymus. CD4(+) T cells. Nat Immunol 2008;9:1122–30.
L-selectin is involved in the recruitment of the newly emerged 17. Wakabayashi Y, Watanabe H, Inoue J, et al. Bcl11b is required for
T cells to lymph nodes. L-selectin interacts with various ligands, differentiation and survival of αβ T lymphocytes. Nat Immunol
including GlyCAM-1 and CD34, expressed by the high endothelial 2003;4:533–9.
venules in the lymph nodes to coordinate movement of the cells 18. Li L, Leid M, Rothenberg EV. An early T cell lineage commitment
38
into the secondary lymphoid organs. Together, these molecules, checkpoint dependent on the transcription factor Bcl11b. Science
2010;329:89–93.
as well as others, deliver mature CD4 and CD8 T cells to the 19. Li P, Burke S, Wang J, et al. Reprogramming of T cells to natural
lymph nodes where these cells can function in adaptive immune killer-like cells upon Bcl11b deletion. Science 2010;329:85–9.
responses. 20. Klein L, Kyewski B, Allen PM, et al. Positive and negative selection of the
T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol
ON THE HOrIZON 2014;14:377–91.
21. Merkenschlager M, Graf D, Lovatt M, et al. How many thymocytes
• Deducing how the T-cell receptor (TCR) senses major histocompatibility audition for selection? J Exp Med 1997;186:1149–58.
complex (MHC) class I versus MHC class II and coordinates the 22. Kisielow P, Teh HS, Bluthmann H, et al. Positive selection of
expression of the appropriate CD8 or CD4 coreceptor, respectively antigen-specific T cells in thymus by restricting MHC molecules. Nature
• Understanding additional molecular events that facilitate negative 1988;335:730–3.
selection of tissue-specific antigens in the thymus 23. Koller BH, Marrack P, Kappler JW, et al. Normal development of mice
• Better tools and markers to study αβ T-cell development and the deficient in β 2 M, MHC class I proteins, and CD8+ T cells. Science
acquisition of innate-like functions prior to thymic export
• Developing strategies to combat thymic involution with age and increase 1990;248:1227–30.
T-cell development, especially following bone marrow transplantation 24. Muller D, Koller BH, Whitton JL, et al. LCMV-specific, class II-restricted
cytotoxic T cells in β 2 -microglobulin-deficient mice. Science
1992;255:1576–8.
25. Cosgrove D, Gray D, Dierich A, et al. Mice lacking MHC class II
Please check your eBook at https://expertconsult.inkling.com/ molecules. Cell 1991;66:1051–66.
for self-assessment questions. See inside cover for registration 26. Grusby MJ, Johnson RS, Papaioannou VE, et al. Depletion of CD4+ T
details. cells in major histocompatibility complex class II-deficient mice. Science
1991;253:1417–20.
27. Kisielow P, Bluthmann H, Staerz UD, et al. Tolerance in T-cell-receptor
REFERENCES transgenic mice involves deletion of nonmature CD4 8 thymocytes.
+ +
Nature 1988;333:742–6.
1. Miller JF. Immunological function of the thymus. Lancet 1961;2:748–9. 28. Mathis D, Benoist C. A decade of AIRE. Nat Rev Immunol 2007;7:645–50.
2. Markert ML, Boeck A, Hale LP, et al. Transplantation of thymus tissue in 29. Villasenor J, Benoist C, Mathis D. AIRE and APECED: molecular insights
complete DiGeorge syndrome. N Engl J Med 1999;341:1180–9. into an autoimmune disease. Immunol Rev 2005;204:156–64.
3. Markert ML, Marques JG, Neven B, et al. First use of thymus 30. Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological
transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 self shadow within the thymus by the AIRE protein. Science
cases. Blood 2011;117:688–96. 2002;298:1395–401.