Page 140 - Clinical Immunology_ Principles and Practice ( PDFDrive )

122 ParT ONE Principles of Immune Response

the various steps of T-cell development, including CD4 T-cell KEY CONCEPTS
delineation. 16
Positive Selection and Negative Selection
B-Cell Chronic Lymphocytic Lymphoma/ • Positive selection promotes the survival of double-positive (DP) thy-
Lymphoma 11B (Bcl11b) mocytes whose αβ T-cell receptor (TCR) can interact with MHC–self
Although Notch, TCF-1, and GATA-3 are all essential in promoting peptide complexes expressed by the thymic cortical epithelial cells.
the T-cell lineage, an additional molecule, the transcriptional • Negative selection deletes self-reactive T cells from the repertoire by
repressor Bcl11b, is important in suppressing alternative inducing apoptosis in thymocytes expressing an αβ TCR with high
fates. Bcl11b is only expressed in T-cell progenitors, and it is affinity for self peptides, promoting central tolerance.
not expressed in other hematopoietic cells. This molecule is
upregulated as early as the DN2 stage of differentiation. It
is necessary for T-lineage commitment, but it does not control POSITIVE AND NEGATIVE SELECTION
the expression of many T lineage–specific genes. 17,18 Bcl11b is
necessary to suppress the myeloid potential in the developing Following the productive rearrangement and pairing of an αβ
T-cell progenitors, and interestingly, in mice, deletion of Bcl11b TCR, the DP T-cell precursor must pass through multiple
from T-cell progenitors results in the cells adopting an alternative checkpoints in the thymus before the cell can be released into
NK cell phenotype. 19 the periphery. These processes, termed positive selection and
negative selection, aim to eliminate T-cell clones expressing self-
reactive, as well as unnecessary, nonfunctional αβ TCRs from
T-CELL RECEPTOR REARRANGEMENT the host. This is critical, as rearrangement of both the α and
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AND β SELECTION β TCR genes occurs independent of MHC and antigen (Chapter
5). Therefore the antigen-specificity and the MHC restriction
One key step in T-cell lineage commitment is rearrangement of of any given αβ TCR pair are not predetermined. During both
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a functional TCR, be it an αβ or γδ TCR. Rearrangement of positive selection and negative selection, the ability of the αβ
the TCR gene loci within the developing thymocyte is a highly TCR pair to interact with peptide–MHC complexes is tested
ordered sequence of recombination events mediated by the (Chapter 6), and the strength of the reaction determines the fate
recombinase activating gene (RAG) enzymes (Chapter 4). RAG of the cell.
proteins are induced early in DN thymocytes and initiate
recombination of the TCR γ, δ, and β genes. VDJ (or VJ) Positive Selection
recombination of these loci must yield successful, in-frame Positive selection refers to the ability of the αβ TCR on the DP
rearrangements or the cell will stall at this stage and die. thymocyte to interact with self peptide–MHC complexes expressed
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by the cortical epithelial cells of the thymus. If the αβ TCR is
γδ T cells unable to bind the peptide–MHC complex, the DP thymocytes
For cells of the γδ T-cell lineage, signaling via the newly rearranged will not receive the appropriate signal and thus die by neglect
γδ TCR complex directs the maturation and export of in a matter of days. This is the fate of the majority of DP thy-
the γδ T cell into the periphery. This developmental checkpoint mocytes for two main reasons: MHC alleles are highly diverse,
is critical for the selection of the γδ T-cell repertoire and, if and rearrangement of both α and β TCR genes is random. The
unsuccessful, the thymocytes may either die or be redirected to combination of these two factors does not favor the generation
the αβ lineage. of an αβ TCR pairing capable of binding the peptide–MHC
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complex with appropriate affinity. If, however, the interaction
αβ T cells is successful, the cell is rescued from programmed cell death.
For cells that will enter the αβ T-cell compartment, the devel- Positive selection has been demonstrated experimentally in mice
opmental checkpoints are distinct from that of γδ T cells. Upon that are genetically engineered to express a single αβ TCR with
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productive rearrangement of the TCR β gene, this protein will a known antigen-specificity and MHC restriction. In mice that
pair with preT α chain (surrogate α chain) to create the pre-TCR express the αβ TCR transgene and the correct MHC allele in
complex. The pre-TCR complex associates with the CD3 molecules the thymus, positive selection will proceed, and mature SP T
and induces constitutive signaling within the cells. cells will be exported into the periphery. In contrast, if the mice
do not express the appropriate MHC allele, the αβ TCR transgenic
β Selection and the Appearance of DP thymocytes will fail positive selection and die by neglect in
Double-Positive Thymocytes the thymus.
Signaling by the pre-TCR complex in DN thymocyte facili- Importantly, the positive selecting MHC molecule, be it MHC
tates the process of β selection, which instructs the cell class I or MHC class II, dictates expression of the corresponding
to undergo a burst of proliferation and suppresses further CD8 or CD4 coreceptor that will be retained by the DP thymocyte
β−chain rearrangement. After β selection, the thymocytes as it matures (Fig. 8.2). In mice that lack MHC class I complexes,
will begin to coexpress both CD4 and CD8 on the cell surface. selection of CD4 SP cells proceeds normally, but CD8 SP cells
These cells are termed DP cells. They subsequently initiate are not generated. 23,24 Likewise, in mice deficient in MHC class
recombination of the TCR α gene loci. As a result of the orga- II expression, CD8 SP cells develop and mature, but CD4 SP
nization of the TCR α loci, DP thymocytes have multiple cells do not. 25,26 Notably, positive selection of DP thymocytes
opportunities to generate a successful TCR α rearrangement. cells can be rescued in MHC-deficient hosts by restricting MHC
Consequently most DP thymocytes express an αβ TCR. Only a expression to the thymic cortical epithelial cells, and this dem-
fraction of these cells will progress into the periphery as CD4 onstrates the crucial role of MHC and the cortical epithelial cells
or CD8 SP T cells. of the thymus in regulating T-cell development.