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Yale Article (Editorial)
Do Natural T Cells Promote Liver Regeneration?


Hepatology, April 2000, p. 1022-1024, Vol. 31, No. 4

Early research on T lymphocytes defined them as thymus-dependent cells (hence the designation "T") that express an immunoglobulin-like two-chain antigen receptor (the TCR). The ligand-binding alpha and beta chains of this TCR do not possess signaling domains and transmit activation signals through a complex of associated transmembrane proteins, collectively called CD3. These cells are key components of adaptive immunity, express very diverse receptors, and are capable of enormous clonal expansion in response to an antigenic challenge. The relative expansion of specific T lymphocytes is part of the mechanism whereby a faster, more effective memory response is delivered on second encounter with an antigen.

In contrast to these T cells, interest is growing in a diverse group of cells that express T-cell-like recognition structures but do not appear to show the massive clonal expansion and immunological memory of normal CD4+ and CD8+ T cells. These cells include a population that shares properties of natural killer (NK) cells and alpha-beta T cells (termed NK-T cells) and several distinct subsets of cells that express CD3-associated receptors associated with two distinct ligand-binding chains, gamma and delta. These cells may be collectively termed "natural T cells," because their effector functions are not enhanced by earlier exposure to the same antigen (i.e., they do not show immunological memory). Although the molecular structure of the receptors on these cells is well understood, their biological functions are much less clear. A report published in this journal, taken together with other information from the literature, suggests a unified model for the function of both the NK-like T cells, and the gamma-delta T cells, which together comprise the natural T cell grouping.

The liver displays extraordinary powers of regeneration after injury, but the mechanism underlying this capacity is not well understood. In this issue of HEPATOLOGY, Minagawa et al. report that the regeneration of the liver after partial hepatectomy is accompanied by a large increase in the numbers of T-cell receptor-intermediate, mainly NK-like T cells. Further, they report that this increase is dependent on signaling through adrenergic receptors, because both the beta-blocker, propranolol, and the alpha-blocker, phentolamine, inhibit the accumulation of these T cells. The lymphocytes isolated from regenerating liver displayed increased cytotoxic activity, which the investigators measured by using both thymocytes and hepatocytes as targets.

Sympathetic Neuron Adrenal Diagram

Fig. 1.   A hypothesis provoked by the work of Minagawa et al., in which an adrenergic damage signal travels either locally (via sympathetic neurons) or systemically (via secretion of sympathetic hormones) and recruits natural T cells to the damaged liver. These cells then participate in promoting cell division and tissue repair. In the Figure, NK-T cell no. 1 is secreting growth factors, cell no. 2 is promoting the growth and function of other NK-T cells, and cell no. 3 is delivering a direct costimulatory signal through a receptor-ligand interaction with the hepatocytes.

This is a very interesting study that raises many issues in liver immunobiology and tissue repair. First and foremost is the possible role of NK-like T cells in liver regeneration. This lymphocyte subset is rare in most tissues, but unusually abundant both in bone marrow and in the liver.1,2 These cells are present in both mice and humans, and their common properties include the coexpression of a TCR and NK-like markers (NK-1.1 in mice and CD56 and CD57 in humans), an extremely limited TCR repertoire in which the TCR alpha chains are essentially monomorphic (V alpha 14, J alpha 281 in mice; V alpha 24, J alpha Q in humans), and the recognition of glycolipid antigens presented by CD1 molecules.3,4 CD1 molecules are expressed on hematopoietic cells, on intestinal epithelium, and on hepatocytes,5,6 which may explain the prevalence of NK-T cells in the bone marrow and liver. Their effector functions include the secretion of diverse cytokines, including interferon gamma and interleukin 4, and cytotoxicity delivered both through the perforin pathway and through cell surface Fas ligand (FasL).7-9

The observation that adrenergic receptor blockers inhibit the accumulation of NK-T cells in the regenerating liver suggests that these cells are activated as part of a "stress response." The limited diversity of their TCR and its specificity for glycolipids presented by CD1 suggest that these ligands may be "damage signals" that recruit the cells, whatever the mechanism of tissue injury might be. This property may be shared with several subsets of gamma-delta T cells, which also express antigen receptors of limited diversity. In the skin, dendritic epidermal T cells are gamma-delta cells expressing a V gamma 3, V delta 1 receptor with no junctional diversity.10 These cells respond to an antigen expressed on keratinocytes11 and are believed to be involved in the detection of skin damage and in repair.12 Similarly, intestinal gamma-delta cells do not appear to be actively involved in the defensive immune response to the bacterial pathogen Eimeria vermiformis, but are important in limiting tissue damage.13 In a different infection of a different organ, gamma delta cells appear to limit tissue damage due to the granulomatous response to Mycobacteria tuberculosis infection of the lung14 and also damage caused by ozone toxicity.15 Thus, several populations of unconventional "natural" T lymphocytes have documented roles in the maintenance of tissue integrity. This creates a precedent for the involvement of NK-T cells in liver regeneration.

The expression of adrenergic receptors on lymphocytes is an old story (see, for example,Galant et al.16), but the biological significance of such expression is not understood. From the report by Minagawa et al., it is not clear whether the alpha and beta blockers are acting on local neurotransmitters released from sympathetic neurons in the liver itself, or on systemic stress hormones such as noradrenaline. Both alpha and beta adrenergic receptors appear to suppress the activation of conventional T cells,17,18 although Minagawa et al. argue that adrenergic signals promote the recruitment of natural T cells. These two cell types may therefore be reciprocally regulated. In support of this position, other evidence suggest that intrahepatic natural T cells are promoted by estrogen in contrast to thymocytes, which respond to estrogen with apoptosis.19

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Adrenal Insufficiency

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