The Tcell Receptor Complex

Two types of T-cell receptor (TCR) are expressed on mature T lymphocytes, either a heterodimer composed of a- and P-chain glycoprotein subunits (majority of T cells) or of y and 8 chains (less than 1 to 20 percent of T cells), which can be distinguished with specific antibodies. Clonotypic TCR chains associate non-covalently with multiple signal-transducing subunits, including the CD3y, CD38, and CD3e molecules and members of the Z family of proteins, the last being essential for efficient surface expression of the TCR and CD3 components.267 Typically, CD3,y/8 T lymphocytes lack both CD4 and CD8 expression, whereas virtually all CD3,a/P T cells express either CD4 or CD8. During early T-cell development, TCR-8 genes rearrange first at the stage of CD34+CD2+CD5+CD1a-immature thymocytes preceded by the expression of intranuclear TdT and the synthesis of cCD3, immediately followed by TCR-y1 and -y2 and in most cells TCR-P gene rearrangements in CD34+CD2+ CD5+CD1a+ cells.268 Transcription of functional TCR-8 and TCR-y arrests the expression of TCR-a, whereas unproductive rearrangement of 8 and/or y genes and deletion of TCR-8 allows the rearrangement and transcription of the TCR-a genes. Successful rearrangement of TCR-a and -P genes gives rise to TCR-a/p, which will assemble a CD3,a/p antigen receptor complex that will be expressed in the plasma membrane, analogous to the CD3,y/8 complex. Although no other pairwise combinations of TCR chains have been seen on the surface of normal T cells, CD3,a/p cells may contain functional or sterile Y or 8 transcripts in their cytoplasm. In leukemia, expression of TCR-P glycoprotein in the cytoplasm of CD3,y/8 cells and membrane appearance of a p/8 receptor have been observed.261 Contrary to the high frequency of cross-lineage somatic gene rearrangements seen in ALL, TCR gene rearrangements are not seen in normal B-cell precursors.269 This finding demonstrates the danger in extrapolating data from leukemic cells to explain phenomena occurring during normal hematopoiesis.

Chromosomal aberrations in leukemias that involve Ig or TCR loci are highly predictive of the immunophenotype. The IgH locus is at 14q32, IgK maps to 2p12, IgA to 22q11, TCR-a and 8 genes are located on chromosome 14q11, the TCR-fi genes on chromosome 7q35, and the TCR-y genes on chromosome 7p14.

Developmental Hierarchy of Antigens Expressed During T/Natural Killer Cell Development and Their Putative Physiologic Function

The thymus is believed to play a central role in the development of the T cell. However, it is well accepted that thymic precursors are derived from bone marrow, because pluripotent stem cells of the CD34+CD38- phenotype have not been identified in fetal or pediatric thymuses.270-273 The earliest thymic CD34highCD45RA+CD90+ precursors cells have the ability to differentiate into various lineages, including T cells, dendritic cells (DCs), and NK cells. Even the CD34+CD2+CD5+ thymic precursor population still contains T/NK differentiation potential. Sequential developmental stages demonstrate populations differing in the intensity of CD33 and CD7 expression, despite similar CD2, CD5, and CD38 expression.272-274 The study by Márquez et al.274 suggests that upregulation of CD44 and CD13 on CD34+CD5+CD33low thymic precursors cells is the necessary step common to both NK cells and DC to diverge from the T-cell lineage. CD1a expression characterizes the earliest committed T-cell progenitors in the thymus. Although these cells express intracytoplasmic CD3, they still lack surface CD4 and CD8 expression. Subsequently they acquire CD4 before CD8.272 The CD34+TdT+CD7+CD2- brightly expressing CD62L (LECAM-1) population in fetal and adult bone marrow contains precursors to CFU-TL (T-lymphocyte CFU)187>270 and NK cells.275 Subsequent events include the appearance of CD2 and CD5, followed by cCD3 in CD34+ precursor cells. Differentiation of T cells is characterized by the transient expression of CD1a; a brief early upregulation of CD10 on CD34+ progenitors just before the surface expression of the CD3/TCR complex, which is analogous to its upregulation and subsequent loss at the time of sIgH expression during B-cell differentiation; and the loss of CD34 concomitant with the appearance of CD4 and CD8 and prior to the acquisition of sCD3. With the development from double CD4+/CD8+ immature to single-positive (CD4+ or CD8+) mature T cells and their export into the peripheral blood, the CD38 antigen is lost, as seen during B-cell differentiation, and adhesion molecules involved in T-cell homing such as CD62L and CD44, are upregulated.270 Usually 95 percent or more of mature, circulating T lymphocytes express CD3, TCRa/p, and 5 percent or less express CD3, TCRy/8. Typically, the majority of y8 cells lack CD4, CD8, and often CD5. In contrast, the rare subtype of TCRy8+ T-ALL displays heterogeneity in terms of its T-lineage antigen expression patterns.276,277

The CD34+CD7+ and CD34+CD7+CD2+ bone marrow precursor cells represent direct intermediates in NK cell devel-opment.275 Subsequent differentiation along the NK-cell lineage results in expression of CD16 and CD56. Although adult

NK cells do not rearrange TCR genes and do not express TCR proteins in their cytoplasm or their cell surface, NK cells from fetal liver and cord blood have been found to express CD3,S and CD3,e proteins in the cytoplasm.278 Data on clonal TCR gene rearrangements in lymphoid NK-cell leukemia are inconsistent.250

With respect to putative or established physiologic functions of T-cell and NK-cell antigens, the reader is referred to the Proceedings of the Leucocyte Typing Conferences II to VII.60-65 CD1 proteins comprise different isotypes (CD1a, 1b, 1c, 1d, 1e) with unique properties in the immune system, related to but distinct from those of major histocompatibility complex-encoded molecules.279 Rather than presenting peptide fragments of antigens, CD1 proteins allow T cells, particularly of the rare CD4-CD8- phenotype, to respond to lipids and glycol-ipids. CD1a characterizes the cortical thymocyte stage of T-lin-eage ALL, which in adults and children has improved event-free survival when compared with other T-ALL subgroups.31,280

For its function as the mediator of adhesion, CD2 was initially called the sheep red blood cell receptor. The prototype lig-and for CD2 is the leukocyte-function-antigen (LFA)-3 or CD58; more recently identified ligands include other GPI-linked structures, namely CD48 (BLAST-1) and CD59, as well as CD15. Expression of CD2 is not limited to T-lymphocytes, in that it is found on a portion of immature and mature B-lym-phocytes as well as NK-cells. In acute leukemia, absence of CD2 is a frequent occurrence in T-ALL and associated with decreased survival.281,282 CD2 expression in B-lineage ALL, in the absence of any other T-cell markers, occurs in less than 5 percent of all ALL cases and may be associated with favorable clinical features, at least in children.283

The CD7 antigen is a member of the Ig supergene family involved in T-cell activation and cellular adhesion. In accordance with its features as a hematopoietic stem cell marker,183,184,189 CD7 is expressed on the leukemic lym-phoblasts from the vast majority of T-lineage ALL cases, in a substantial fraction of AML cases, and rarely in B-lineage ALL. A small subset of normal human blood T lymphocytes has been demonstrated to lack CD7. These CD3+CD4+CD7- lymphocytes have been discussed as the normal counterpart to the malignant cells in cutaneous T-cell lymphoma, such as Sezary syndrome.284,285

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