T-bet: the first master regulator for lymphocyte homing commitment?

Comment on Lord et al, page 3432

In this issue, Lord and colleagues demonstrate a role for the transcription factor T-bet in coordinating the paired expression of 2 independent homing molecules: adhesion receptor P-selectin ligand (P-lig) and chemoattractant receptor CXCR3.

Lymphocyte subpopulations express heterogeneous arrays of homing molecules, including various types of chemoattractant and adhesion receptors. In the early 1990s, the leukocyte trafficking field introduced the concept of the homing “area code,” in which the combination of homing molecules expressed by a given cell type determines its preferred target tissue.^1,2  The pattern of adhesion and chemoattractant receptors expressed by a leukocyte cell type thus embodies a multidigit routing code, directing blood-borne cells specifically to those tissues whose endothelial lumens display the reciprocal ligand combination. In other words, the combination of receptors expressed by a cell is equally as important as the presence or absence of any single receptor. There are several examples of adhesion and chemoattractant receptor combinations believed essential for homing to particular tissues: CD62L + CC chemokine receptor 7 (CCR7), for targeting naive T cells to peripheral lymph nodes through high endothelial venules (HEV)³ ; CLA (cutaneous lymphocyte antigen) + CCR4, for targeting cutaneous memory T cells to sites of inflamed skin⁴ ; and α4β7-integrin + CCR9, for targeting gut-specific memory T cells to the small intestine.⁵ 

Memory and effector T cells usually express arrays of homing molecules that differ greatly from those of the naive T cells from which they originated. Dendritic cells within lymphoid organs are believed to “imprint” naive T cells with this new array upon first exposure to cognate antigen. However, the mechanisms by which these changes are initiated and the transcription factors controlling these differentiation pathways remain largely unexplored.

T-bet is a transcription factor associated with T helper 1 (Th1) and natural killer (NK) differentiation.⁶  Lord and colleagues discovered that, unlike wild-type (WT) cells polarized under standard Th1 conditions, T-bet–deficient Th1 cells were unable to home to inflamed peritoneum in vivo. This deficiency correlated with inability to bind P-selectin or respond to the chemokine ligands of CXC receptor 3 (CXCR3). Ectopic expression of T-bet restored normal P-selectin ligand (P-lig) and CXCR3 expression in Th1 cells, but interestingly, also induced their expression in T-cell types that would not normally express these receptors.

It is not presently clear which types of tissue-specific homing pathways require expression of the P-lig + CXCR3 combination, but some types of inflammation are known to induce ligands for these receptors within various tissues. The present study certainly implies that one or both of these molecules are required for homing to inflamed peritoneum.

P-lig is a very complex molecule, which requires the sulfation of carbohydrates primarily found on the protein P-selectin glycoprotein ligand-1 (PSGL-1). The present study demonstrates that the mRNA levels of a necessary sulfation enzyme, tyrosyl protein sulfotransferase-2 (TPST-2), are influenced by T-bet. The study also demonstrates that T-bet affects CXCR3 mRNA expression. Thus, T-bet appears to coordinate the expression of cell surface P-lig and CXCR3 by reducing the transcription of 2 very different molecules: the sulfation enzyme TPST-2 and the chemokine receptor CXCR3.

The effects of T-bet on homing molecules appear to be quite specific for the P-lig + CXCR3 combination. Expression of CLA, structurally related to P-lig, is not influenced by T-bet in this system. Further, chemokine receptors other than CXCR3, including CCR4, CCR5, CCR7, and CXCR4, are unaffected.

Thus, T-bet may be the first example of a master regulator for a lymphocyte homing program, coordinating the expression of an adhesion receptor/chemoattractant receptor combination. This finding may give impetus to the lymphocyte-trafficking field for identifying master regulators of other tissue-specific differentiation pathways. Successful migration of T cells to a specific target site is a major determinant of immunologic outcome. The ability to manipulate the homing tropisms of lymphocytes will be a significant boon for rational design of treatments for tissue-restricted autoimmune diseases (ie, psoriasis, Crohn disease), as well as design of immunization strategies to protect against tissue-tropic organisms. ▪