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Blood, 15 July 2005, Vol. 106, No. 2, pp. 393-394.
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TRANSPLANTATION
Comment on Maeda et al, page 749
Host   T cells: an innate bridge to the epithelial targets of GVHD?
Geoffrey R. Hill
THE QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
Host   T cells are shown to be a critical population for the activation of host antigen-presenting cells and subsequent induction of graft-versus-host disease (GVHD).
The characteristic tissue distribution of acute GVHD has long puzzled researchers and clinicians alike. In this issue of Blood, Maeda and colleagues provide a potential explanation for acute GVHD's predilection for the skin and intestinal tract. The authors demonstrate that host T cells, which predominate in these organs, play an important role in the activation of host antigen-presenting cells (APCs) following total body irradiation. These fully activated host APCs in turn stimulate alloreactive donor   T cells, unleashing the subsequent tissue injury characteristic of GVHD.1
So how do T cells differ from T cells and what is their physiologic role in immunity? Although T cells represent only a small proportion (< 5%) of lymphocytes in the blood and peripheral lymph nodes, they are present in much larger numbers in epithelial tissues such as the skin and intestinal tract. They are unique in that they recognize both protein and nonprotein moieties in the absence of major histocompatibility complex (MHC) and thus are not dependent on antigen processing by APCs. The predominant antigens that T cells recognize and the requirement for the T-cell receptor (TCR) in this process remain unclear. To date, the epithelial-associated T cells are known to be capable of recognizing constitutively expressed "self"-antigens such as the MHC class I polypeptide-related sequences and the T10/22 proteins, the latter of which are expressed in stressed epithelial cells in response to inflammation. It is clear that epithelial-based T cells can release proinflammatory cytokines and chemokines to augment mucosal immunity early in the immune response.2 Conversely, they are also a critical immunoregulatory population late in immunity, helping to terminate the immune response through the production of anti-inflammatory cytokines such as interleukin-10 (IL-10).3
Thus, it appears likely that, following total body irradiation, host T cells sense damage to stressed epithelial tissue in the skin and intestine to which they are juxtaposed and subsequently activate host APC trafficking through the tissue (see figure). The mechanism(s) by which host T cells activate host APCs remains to be defined but appears to require cell-to-cell contact, at least in vitro according to Maeda and colleagues. The fully activated recipient APC then traffics to the regional lymph node to initiate the activation and expansion of alloreactive donor T cells, which are in turn attracted back to the intestine, perhaps by virtue of the chemokines secreted by the T cell. The final effector phase of tissue injury is then mediated by a combination of cytolytic pathways and inflammatory cytokines downstream of the donor T cell.4 The mechanisms by which T cells are activated during allogeneic transplantation and their subsequent enhancement of host APC allostimulatory capacity will be important avenues for future study. From a clinical perspective, the current study suggests a novel approach to GVHD prophylaxis: the specific deletion of recipient T cells prior to transplant conditioning. 
References
- Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen presenting cells. Science. 1999;285: 412-415.[Abstract/Free Full Text]
- Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002;2: 336-345.[CrossRef][Medline]
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- Hayday A, Tigelaar R. Immunoregulation in the tissues by gammadelta T cells. Nat Rev Immunol. 2003;3: 233-242.[CrossRef][Medline]
[Order article via Infotrieve]
- Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a target organ of graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95: 2754-2759.[Abstract/Free Full Text]
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