Evidence for clonal selection of gamma/delta T cells in response to a human pathogen.

Abstract

SummaryT cells bearing y/b antigen receptors comprise a resident population of intraepithelial lymphocytes in organs such as skin, gut, and lungs, where they are strategically located to contribute to the initial defense against infection . An important unsolved question about antigen-driven y/b T cell responses regards the breadth of their T cell receptor (TCR) repertoire, since many specific epithelial compartments in mice display limited diversity. We have examined the diversity of TCR S gene expression among human y/b T cells from skin lesions induced by intradermal challenge with Mycobacterium leprae . We show that the vast majority of'y/b cells from M. leprae lesions use either V61-J61 or V62 -J61 gene rearrangements and, within a given region of the lesion, display limited junctional diversity. This contrasts markedly with the extensive diversity of y/b T cells from peripheral blood of these same individuals, as well as skin from normal donors . These results indicate that they/b response to M. leprae involves the selection of a limited number of clones from among a diverse repertoire, probably in response to specific mycobacterial and/or host antigens . O ne of the fundamental aspects of cellular immunology is the selection and clonal expression of T cells bearing specific receptors by antigens. While the selection of ci/(3 T cells has been studied in detail, little is known about the selection of y/b T cells by antigen . The genetic diversity of the TCR provides a measure of the scope of the T cell repertoire. In contrast to the a/a TCR, the germline gene segment diversity for both the TCR y and S chains is small . The further limitation of this diversity by the preferential usage of only a few variable (V) genes or V gene pairs at specific anatomical locations (1-3) suggests a particularly narrow TCR repertoire, likely reflecting recognition of a limited number of ligands . On the other hand, there is unprecedented junctional diversity, particular in the b chains of this receptor (4-6) . We reasoned that analysis of the TCR y/b repertoire of a specific immune response would provide clues about the set of antigens recognized : whether diverse or limited, conventional, or superantigen-like. The presence of antigen-reactive TCR -y/6-bearing cells in leprosy skin lesions (7) provides a unique in vivo model to examine the y/b receptor repertoire at the site of immunopathologic reaction .Much experimental evidence indicates that y/b T cells contribute to the granuloma formation in response to mycobacterial infection (7) . First, TCR y/b cells comprise a strikingly high percentage of the T cell population in infectious disease lesions that contain recently formed granulomas. These include lepromin skin tests (Mitsuda reactions), which are experimental DTH reactions induced by intradermal injection of Mycobacterium lepme, reversal reactions in leprosy, which represent a naturally occurring DTH response to M. leprae, and localized American cutaneous leishmaniasis. Second, the y/b T cells from these infectious l...

Implication of γδ T cells in the human immune response to cytomegalovirus

“…This apparent absence of Vγ9-Vδ2 T-cell involvement is not due to an anergic status as previously proposed for Vγ9-Vδ2 T cells in HIV + patients (48), as such cells still proliferated strongly in response to mycobacterial antigens (data not shown) (16). Whereas abnormal expansion of Vδ3 cells has not been reported thus far, that of Vδ1 cells has been observed in several chronic inflammatory diseases (14,52,53) and occasionally in infectious diseases (12,13,(49)(50)(51). Expansion of Vδ1 cells is generally restricted to anatomical sites affected by the disease and is seldom associated with an increase in peripheral blood.…”

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

“…Most of these studies are related to infections such as Listeria monocytogenes, Salmonella choleraesuis, Mycobacterium tuberculosis, M. leprae, influenza virus, and Candida albicans (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In these circumstances it is not always clear whether ␥␦ T cell Ag receptors are recognizing foreign Ags or interacting with self-ligands whose expression is induced by infection.…”

Peripheral selection of V delta 1+ cells with restricted T cell receptor delta gene junctional repertoire in the peripheral blood of healthy donors.

“…In the present work, we have shown that V81-J81junctions, while displaying the extensive alterations of germline sequences that are characteristic of post fetal stages (14), are not randomly represented among PBL V/$1 + cells in a large fraction of healthy donors. The description of such repeated sequences in the PBL of healthy donors is unprecedented since only a few V81-J81 sequences have been published to date (28)(29)(30)(31). Two studies showed an unrestricted repertoire in PBL from patients and normal controls, but predominant sequences in acute multiple sclerosis (29) and leprosy lesions (28), respectively, suggesting in situ selection of particular VIS1 + cells by so far undefined antigens.…”

“…The description of such repeated sequences in the PBL of healthy donors is unprecedented since only a few V81-J81 sequences have been published to date (28)(29)(30)(31). Two studies showed an unrestricted repertoire in PBL from patients and normal controls, but predominant sequences in acute multiple sclerosis (29) and leprosy lesions (28), respectively, suggesting in situ selection of particular VIS1 + cells by so far undefined antigens. One further study demonstrated a restricted V/~I repertoire in the peripheral blood of certain patients with rheumatoid arthritis but not in four healthy controls (30).…”