Transcript TCR rearrangement and selection in the thymus

Part II Lecture on TCR rearrangement and
selection in the thymus
22nd November 2012
by
Mike Clark, PhD
Reader in Therapeutic and Molecular Immunology
Department of Pathology
Division of Immunology
Cambridge University
UK CB2 1QP
www.antibody.me.uk
ab and gd T-cells
• See earlier lecture on TCR genes and rearrangements
•
a and d locus on the same chromosome so rearrangement
of one results in isotypic exclusion of the other
 gd cells have more limited number of segments but much
more variability in CDR3
 ab cells are the major population and the majority see
antigen as peptide presented in the context of MHC-class I
and class II molecules
• A smaller proportion of T-cells see alternative antigens
MHC restricted ab TCR
Mucosal-associated invariant T-cells
MAIT
• Subset of ab T cells in humans and mice
which are DN (CD4- CD8-)
• Restricted by non-polymorphic, nonclassical MHC molecule MR1
• Over expression of (semi) invariant TCRa
chains and b chains
• Secrete g-interferon and Il-17
• Reviewed by Bourhis et al (2011) Trends
in Immunology 32: 212-218
NKT-cells
• Have properties of both T-cells and NK-cells
• Express a (semi) invariant abTCR
• Recognition of lipids and glycolipids presented by CD1d
• Can express FcgR CD16, CD56, NK1.1
• Produce g-interferon, IL-4, IL-2, TNF-a
• Role in immunity against bacteria such as mycobacterium
• Review by Jerud et al (2006) Transfusion Medicine and
Hemotherapy 33:18-36

doi:10.1159/000090193
gd-T cells
• Smaller subset of T-cells ~2%
• Higher abundance in gut mucosa (intraepithelial
lymphocytes IELs)
• Not MHC restricted and may be able to recognise
whole proteins and phosphoantigens
• A sizeable population of mouse gd T-cells
recognise the non-classical class-1 T10 and T22
• Reviewed in Chien & Konigshofer (2007)
Immunological Reviews 215: 46-58
Antigen recognition by γδ T cells
Immunological Reviews
Volume 215, Issue 1, pages 46-58, 2 FEB 2007 DOI: 10.1111/j.1600-065X.2006.00470.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-065X.2006.00470.x/full#f6
ab T-cell development
• Early thymocyte precursor (ETP) DN1 stage differentiate
into CD44 CD117 (c-Kit)
• DN2 cells become CD25+ and start to rearrange b (or gd)
chains
• DN3a cells lose CD44 expression and characterised by
expression of pre-TCR b chain plus invariant pre TCRa
chain.
• Differentiate into high CD27 expressing DN3b cells and
following pre-TCR selection lose CD25 expression
• DN4 with surface expression of CD24, CD71 and CD98
and start to rearrange a chain
• Diffentiate into DP (CD4+CD8+) cells where positive and
negative selection can take place
Notch regulation of early thymocyte development
Yashiro-Ohtani et al (2010) Seminars in Immunology 22: 261-269 http://dx.doi.org/10.1016/j.smim.2010.04.015
Cortical (cTEC) and medullary (mTEC) epithelial cells regulate distinct stages of T cell development and selection.
Anderson and Takahama (2012) Trends in Immunology 33:256-263 http://dx.doi.org/10.1016/j.it.2012.03.005
cTEC (cortical thymic epithelial cells)
• Responsible for positive selection of ab-TCR (low) DP
cells
• Low affinity induces survival
• Differentiate to TCR(high) SP CD4 or CD8
• High affinity results in programmed cell death
• Unique processing of peptides may occur in cTECs
mTEC (medullary thymic epithelial cells)
•
•
•
•
•
•
•
Expression of chemokine receptors induces positively selected SP
thymocytes to migrate towards the thymic medulla.
TCR engagement in immature SP cells induces TNF superfamily cytokines
such as RANKL (receptor activator of nuclear factor kB ligand)
Receptor for RANKL expressed by mTECs but not by cTECs
mTECs have promiscuous gene expression promoted by the nuclear
protein Aire
Responsible for deletion of autoreactive T-cells
May also get indirect presentation of self-peptides through neighbouring
dendritic cells.
Positively selected thymocytes spend about 4-5 days in the medulla before
being exported to the circulation
gd versus ab T cell development
Ciofani & Zuniga-Pflucker (2010) Nature Reviews Immunology 10:657-663 http://doi:10.1038/nri2820
T-cell development
extra resources and reviews
• YouTube video from Janeway, Garlandscience

http://www.youtube.com/watch?v=odLLr6mjaUQ
• YouTube video from Handwritten tutorials

http://www.youtube.com/watch?v=08H5CmDaRjU
• Lecture notes from Stephen Cobbold in Oxford

http://users.path.ox.ac.uk/~scobbold/Teaching/POSSEL.pdf