Page 1179 - Williams Hematology ( PDFDrive )

1154 Part IX: Lymphocytes and Plasma Cells Chapter 74: Lymphopoiesis 1155

THYMIC PROGENITORS of their biologic importance in lymphopoiesis and their clinical rele-
It was long assumed that lymphoid commitment in the marrow pre- vance in primary immune deficiency disease. The γ subunit is a signal-
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cedes thymic seeding and T-cell development. However, despite the ing component of six different cytokine receptors, interleukin (IL)-2,
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clear existence of lymphoid-committed progenitors within the mar- IL-4, IL-7, IL-9, IL-15, and IL-21, all of which act on dif-
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row, the dominant cell type that migrates from the marrow and seeds ferent stages and pathways involved in lymphopoiesis. All six γ -
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the thymus to initiate thymopoiesis is still a matter of controversy. As dependent receptors are unique in their activation of the Janus kinase
described above, a variety of marrow-derived lymphoid-restricted pro- 3 (JAK3) tyrosine kinase, a molecule that directly interacts with γ to
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genitors and LMPPs are each able to generate T cells in vitro and in mediate signaling. In addition to the γ subunit, each of these recep-
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vivo. However, careful examination of the thymus has revealed primi- tors are comprised of an α subunit through which specific ligands bind;
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tive progenitors that have not only lymphoid, but also myeloid and ery- IL-2R and IL-15R also share a common β subunit.
throid potential. Such rare cells have been identified in murine thymus, Null mutations of γ result in severe combined immunodeficiency
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where they are referred to as early thymic progenitors (ETP), and also (SCID) syndromes in mice and humans. However differences in the
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in human thymus, where they have the phenotype CD34+lin CD1a neg- specific lineages affected reveal important species differences in cytok-
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CD7 . The lineage potential of such cells as well as the sharing of ine dependency. The most important of these differences is in the
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many cell-surface markers and similar gene expression profile to HSCs, requirement for IL-7 signaling in human and murine B-cell develop-
suggest strongly that HSCs or at least multipotent progenitors are able ment. Adult murine B-cell development has an absolute requirement
to seed the thymus directly without a preceding stage of lymphoid com- for IL-7 to IL-7R interaction and subsequent downstream signaling
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mitment in the marrow. Which of these alternative progenitor types involving the γ subunit of the IL-7R and JAK3. In contrast, IL-7 is not
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are dominant in terms of their contribution to steady-state thymo- essential for human B-cell development. X-linked SCID patients with
poiesis is yet to be determined ; however, it is likely that early thymic mutations in the γ cytokine-receptor subunit exhibit profound thymic
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progenitor lineage potential is itself dynamic, based on colonization of hypoplasia and an absence of NK cells but normal or elevated numbers
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the murine thymus with temporally distinct waves of both lymphoid- of B cells. SCID patients with mutations in JAK3 or the IL-7R also
restricted and multipotent thymic-seeding progenitors during embry- have normal numbers of blood B cells. Although B-cell numbers are nor-
onic development. 77 mal, B-cell function in patients with γ -deficient SCID is not normal and
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patients are hypogammaglobulinemic, presumably partly as a result of the
role of IL-4 in B-cell function and the absence of T-cell interactions in
CHALLENGES IN FUNCTIONAL antibody production. These collective results indicate IL-7 is not essential
CHARACTERIZATION OF LYMPHOID for at least the numerically normal development of human B cells.
PROGENITORS NK cells are absent in patients with γ -deficient and JAK3-deficient
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SCID, but are normal in IL-7Rα deficiency. 65,97,98 NK cells are also absent
The accurate assignment of lineage potential to immunophenotypically in mice deficient in IL-15, IL-15Rα, or IL-2Rβ (a subunit shared by
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defined progenitors requires clonal analysis. Although clonal assays for IL-2R and IL-15R), demonstrating the essential role of IL-15, but not
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myelo-erythromegakaryocytic progenitors have existed for more than IL-7, in NK cell development. Although no null mutations for IL-15
30 years, the ability to differentiate HSCs along lymphoid pathways has or its receptor have been described in humans, a familial NK cell defi-
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been relatively recent, particularly for human studies. In vitro assays ciency has been described in humans in which the response to IL-15
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for human lymphoid potential became available when it was observed and IL-2 appears to be subnormal. 102
that selected murine stromal cell lines were capable of supporting B-cell, The production of both B and NK cells in patients with IL-7Rα
NK cell, and DC differentiation from primitive human HSCs. 78–80 T-cell deficiency, shows that in humans IL-7 is not required for the
differentiation systems are more complex, requiring an in vitro model earliest stages of lymphoid commitment or growth of CLPs. This
that recapitulates the unique environment of the thymus. Originally this point is further supported with the finding that multilymphoid
was only possible using the fetal thymic organ culture method, a system CD34+CD38 CD7+ progenitors in human cord blood do not express
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in which large numbers of murine or human progenitors are seeded IL-7Rα, and that early lymphoid progenitor subsets are preserved in
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into whole thymic lobes in so-called hanging drop cultures. A more the marrow of γ and JAK3-deficient patients. In contrast to B cells
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efficient in vitro system for studying murine and human T-cell differ- and NK cells, however, T-cell development is absolutely dependent
entiation has been developed using a murine stromal monolayer that on IL-7 in both mice and humans. In both species, mutations of any
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expresses the Notch ligand Delta-like 1 (“OP9-DL1 stroma”). How- portion of the IL-7 signaling pathway, that is, γ , IL-7Rα, or JAK3, com-
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ever, none of the in vitro T-cell culture systems simultaneously support pletely prevents T-cell development. IL-2, in contrast, although an
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B-cell development, making proof of full T- and B-lymphoid potential important cytokine in proliferation and function of mature T cells, is
at a clonal level technically problematic. In vivo transplantation of a not essential for thymopoiesis; mutations in IL-2, IL-2Rα, or IL2Rβ
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single murine HSC can prove multilineage potential at a clonal level, result in functional T-cell defects, but T cells are not absent.
but this also is technically difficult, especially when studying progenitor
populations that are not self-renewing. In vivo studies with human cells
are particularly challenging as they rely on xenogeneic transplant mod- TRANSCRIPTIONAL REGULATION IN
els with low engraftment efficiency. 41,43 LYMPHOPOIESIS
REGULATION OF LYMPHOPOIESIS The hierarchical differentiation pathways that lead irreversibly to the
diverse array of functionally specialized mature lymphocytes are regu-
lated by groups of genes expressed and repressed in a complex, precisely
CYTOKINES IN LYMPHOPOIESIS orchestrated sequence. As with cytokine regulation, our understanding
The many cytokine pathways that regulate lymphoid development, of which transcriptional factors control each stage of differentiation has
differentiation, and function are too numerous and complex for a full been developed using a combination of gene expression analyses in iso-
description here. However, the cytokine receptors of the common lated progenitors and precursors, and an examination of the functional
gamma (γ ) chain family should be mentioned particularly because consequences of genetic mutations in mice and humans. The review
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Kaushansky_chapter 74_p1149-p1158.indd 1154 9/18/15 2:26 PM