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Blood, 15 March 2008, Vol. 111, No. 6, pp. 2948-2949.
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HEMATOPOIESIS AND STEM CELLS
Comment on Chan et al, page 2953
An ES cell–derived immune system
Michael Kyba
UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER
In this issue of Blood, Chan and colleagues test the limits of the current technology for enabling hematopoietic reconstitution from embryonic stem (ES) cells.
Although the advantages of ES-derived cellular therapies are compelling, the difficulties of turning theory into practice are considerable. Chief among these for the hematopoietic system is that ES cells differentiated in vitro follow an early embryonic program of differentiation, generating hematopoietic stem cells (HSCs) akin to those of the precirculation yolk sac rather than the bone marrow. As the early embryo has no need of lymphocytes, and indeed has neither bone nor marrow, these so-called primitive HSCs are considerably different from the definitive (adult) variety. In particular, they lack the ability to differentiate into T lymphocytes efficiently, and also lack the ability for long-term engraftment in irradiated adult recipients.
Hematopoietic engraftment of these progenitors can be enabled by overexpression of the transcription factor HoxB4.1 Whether this is due to a reprogramming of developmental potential, or is simply a consequence of enhanced self-renewal, is currently unknown. However, it is clear from numerous studies that myeloid cells predominate in the peripheral blood of these recipients, and lymphoid engraftment, although detectable, is minimal.2–4 The question Chan and colleagues ask is: do these few lymphocytes form a true immune system, or are they merely impotent bystanders, expressing the appropriate markers but being too few in number or intrinsically unable to coordinate an immune response? In their experimental system, ES-derived, HoxB4-expressing HSCs marked with GFP to facilitate tracking were transplanted into Rag2–/–  C–/– mice, which lack functional lymphocytes. An immune reaction was then provoked by infection with lymphocytic choriomeningitis virus (LCMV) or vaccination with TNP-conjugated carrier antigens.
In contrast to previous studies, which have monitored lymphocytes in unimmunized mice, infection or immunization elicited a remarkable increase in donor-derived T cells in the peripheral blood. Furthermore, T cells purified from the spleens of LCMV-infected mice could be induced to express IFN- by short-term exposure to the LCMV-specific peptide, NP396-404, demonstrating their epitope-specific activation potential (see figure). The same spleens also contained ES-derived (GFP+) APCs, which, when purified and pulsed with the LCMV peptide antigen, were able to activate T cells from previously infected wild-type mice. It is important to note that the immune reactions elicited in mice that had received transplants, although clearly evident, were much weaker than the same reactions in wild-type mice (compare both the frequency and intensity of IFN- expression in ES-derived versus wild-type splenocytes in the figure). In addition to the T-cell responses provoked by LCMV, transplant-recipient mice were also able to generate TNP-specific antibodies after immunization with either TNP-KLH or TNP-LPS. Again, although clearly evident, these immune responses were attenuated compared with the responses seen in wild-type mice.
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Chimeric Rag2–/–c–/–mice generate peptide-specific T cells after LCMV infection, and hematopoietic progenitor cell (HPC)–derived antigen-presenting cells (APCs) are capable of presenting viral-specific peptide to T cells. See the complete figure in the article beginning on page 2953.
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This work clearly demonstrates the potential ES cells exhibit for immune reconstitution. However, it also makes clear the limitations of using HoxB4 to enable engraftment, and therefore represents a benchmark against which novel methods should be measured.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Kyba M, Perlingeiro RCR, Daley GQ. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 2002; 109:29–37.[CrossRef][Medline]
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- Rideout WM, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 2002; 109:17–27.[CrossRef][Medline]
[Order article via Infotrieve]
- Eckhart S, Leu NA, Bradley HL, Kato H, Bunting KD, McLaughlin KJ. Hematopoietic reconstitution with androgenetic and gynogenetic stem cells. Genes Dev 2007; 21:409–419.[Abstract/Free Full Text]
- Pilat S, Carotta S, Schiedlmeier B, et al. HOXB4 enforces equivalent fates of ES-cell-derived and adult hematopoietic cells. Proc Natl Acad Sci U S A 2005; 102:12101–12106.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell–derived hematopoietic progenitor cells
- Kun-Ming Chan, Sabrina Bonde, Hannes Klump, and Nicholas Zavazava
Blood 2008 111: 2953-2961.
[Abstract]
[Full Text]
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