Self-reactive, T cell receptor-gamma delta+, lymphocytes from the intestinal epithelium of weanling mice.

Intraepithelial T lymphocytes (IEL) are dispersed throughout the intestinal epithelial lining but their role in cellular immune defense is unknown. Their location suggests that their highly activated state may be due to constant exposure to bacterial Ag. To study IEL specificity and function we have prepared a panel of IEL-T cell hybridomas from both adult and weanling C57B1/6 mice. Many of these expressed TCR-gamma delta, a cell type rare in peripheral lymph nodes and spleen but predominant at epithelial surfaces. We have identified a subset of gamma delta T cells from weanling mice which is self reactive, i.e., these hybrids secrete IL-2 spontaneously, without antigenic stimulation or a requirement for APC. Self-reactive TCR-gamma delta+ hybrids and lines, all of which bear a particular TCR (V gamma 1.1C gamma 4V delta 6), have previously been derived from neonatal thymus and the skin. Northern blot and immunoprecipitation analyses suggest that the self-reactive IEL hybrids also bear a C gamma 4/V delta 6 TCR. Antibody inhibition experiments showed that the self-reactivity of the IEL hybrids is TCR mediated. Spontaneous IL-2 production was blocked by soluble anti-CD3 and anti-TCR-gamma delta antibodies but not by antibodies to the TCR-alpha beta. The self-reactive IEL hybrids lack class II MHC and the class I-like proteins CD1 and TLA but express class I MHC. IEL hybrids may also require the vitronectin receptor as an accessory molecule for their activation because spontaneous IL-2 production is blocked by antibody to the vitronectin receptor as well as by the extracellular matrix protein active site peptide RGDS, but not the control peptide RGES. V gamma 1.1C gamma 4V delta 6 T cells in the thymus, skin, and intestine may represent a small and unique subpopulation of lymphocytes with a potential for autoimmune reactivity at peripheral sites.     

In vitro and in vivo activation of murine gamma/delta T cells induces the expression of IgA, IgM, and IgG Fc receptors.

The present studies examined resting and activated murine gamma/delta T lymphocytes, in vitro and in vivo, for surface expression of FcR. Polyclonal gamma/delta TCR+ lymphocytes selectively grown from the spleen and intestine of normal mice did not express FcR when the cells were in a resting state, but when cells were activated with anti-CD3 antibody virtually all of the splenic gamma/delta lymphocytes and a large subpopulation of the intestinal gamma/delta lymphocytes expressed IgA and IgM FcR. This was confirmed by using transgenic mice. Resting gamma/delta TCR+ lymphocytes from the spleen, thymus, lymph node, and blood of gamma/delta TCR transgenic mice did not express FcR for any of the five major classes of Ig H chains. Activation of the gamma/delta TCR+ cells via the CD3/TCR complex induced high levels of IgM and IgA FcR and low levels of IgG FcR. Finally, in hepatic granulomas of schistosome-infected mice, activated gamma/delta TCR+ cells are present and express high levels of IgA and IgM FcR and low levels of IgG FcR. These investigations establish that transition of gamma/delta TCR+ lymphocytes from a resting to an activated state (triggered via the T3Ti TCR complex) is accompanied by the induction of surface membrane receptors specific for Ig H chain isotypes. The activation-linked expression of FcR on gamma/delta TCR+ lymphocytes provides potential mechanisms for coupling the functional activities of gamma/delta T lymphocytes with immune mechanisms that involve Ig molecules, such as antibody-dependent cellular cytotoxicity.     

Age-dependent increase of extrathymic T cells in the liver and their appearance in the periphery of older mice.

The liver is a major site of generation of extrathymic T cells with unique properties (e.g., expressing intermediate TCR and containing self-reactive clones). We investigated herein whether the levels of extrathymic alpha beta T cells varied in various organs as a function of age. A systematic examination of the number of mononuclear cells in various organs of BALB/c mice revealed that the number of hepatic MNC increased with age whereas the number of thymocytes decreased. These changes were more striking in mice fed under conventional conditions than under specific pathogen-free condition. The age-dependent changes in the number of mononuclear cells in the spleen and lymph nodes were minimal. Although the total proportion of alpha beta T cells in each organ remained constant, the staining patterns of TCR-alpha beta as shown by immunofluorescence profiles varied. The most prominent change was that intermediate TCR-alpha beta cells, which constituted a small population in the liver of young mice, expanded in the liver of older mice. Intermediate TCR cells appeared even in the periphery of older mice. These findings were confirmed by the appearance of extrathymic T cells with other unique properties, e.g., double-negative CD4-8- phenotype and CD44 expression. In athymic nude mice, only intermediate TCR cells were present in the liver and periphery. An age-dependent increase of intermediate TCR cells was also seen in these mice. Taken together with the result of bromodeoxyuridine-injection experiment, which showed an intensive in vivo proliferation of cells in the hepatic sinusoids, extrathymic T cells may differentiate predominantly in the liver and appeared even to the periphery in older mice.     

Reciprocal T cell responses in the liver and thymus of mice injected with syngeneic tumor cells.

We investigated the T cell responses in various tissues, especially in the liver and thymus, of mice injected with syngeneic tumors. This study was undertaken since recent evidence indicated that the liver is one of the important immune organs for T cell proliferation. When C3H/He mice were intraperitoneally injected with mitomycin-treated syngeneic MH134 tumors (1 x 10(7)/mouse), a transient increase of liver mononuclear cells (MNC) was induced, showing a peak at Day 4 after injection. Histological study of such liver showed a sinusoidal dilatation and an accumulation of MNC in the sinusoids. The most predominant MNC induced were double negative (CD4-8-) alpha beta T cells and gamma delta T cells. These gamma delta T cells varied, showing unique time-kinetics. Despite a continuous increase of whole liver MNC and alpha beta T cells, the proportion of gamma delta T cells in the liver decreased beginning 4 days after injection. In contrast with the response in the liver, a striking decrease in the cell number of thymocytes was induced after tumor injection, showing a basal level at Day 6. This hypocellularity in the thymus appears to be an inverted response of the lymphocytosis in the liver. At this time, a corresponding decrease in the proportion of double positive (CD4+8+) T cells was always seen in the thymus. Analysis of cell proliferative response showed that the increase of liver MNC after tumor injection was accompanied by augmented proliferation, whereas the decrease of thymocytes was accompanied by depressed proliferation. The present results indicate that there exists a unique, reciprocal response of T lymphocytes between the liver and thymus, and that the presence of tumor appears to stimulate T cell response in the liver but alternatively inactivates such response in the thymus.     

IL-4-producing gamma delta T cells that express a very restricted TCR repertoire are preferentially localized in liver and spleen.

IL-4-producing gamma delta thymocytes in normal mice belong to a distinct subset of gamma delta T cells characterized by low expression of Thy-1. This gamma delta thymocyte subset shares a number of phenotypic and functional properties with the NK T cell population. Thy-1dull gamma delta thymocytes in DBA/2 mice express a restricted repertoire of TCRs that are composed of the V gamma 1 gene product mainly associated with the V delta 6.4 chain and exhibit limited junctional sequence diversity. Using mice transgenic for a rearranged V gamma 1J gamma 4C gamma 4 chain and a novel mAb (9D3) specific for the V delta 6.3 and V delta 6.4 murine TCR delta chains, we have analyzed the peripheral localization and functional properties of gamma delta T cells displaying a similarly restricted TCR repertoire. In transgenic mice, IL-4 production by peripheral gamma delta T cells was confined to the gamma delta+9D3+ subset, which contains cells with a TCR repertoire similar to that found in Thy-1dull gamma delta thymocytes. In normal DBA/2 mice such cells represent close to half of the gamma delta T cells present in the liver and around 20% of the splenic gamma delta T cells.     

Gamma/delta T cell receptor positive T cells in the inflammatory joint: lack of association with response to soluble antigens

In patients with inflammatory synovitis, the proliferative response by lymphocytes from synovial fluid to soluble mycobacterial antigens is enhanced relative to those from peripheral blood. Earlier studies suggested that gamma/delta T cell receptor positive (TCR+) T lymphocytes may significantly contribute to the mycobacterial-specific synovial fluid response. We therefore examined the relationship of the T cell proliferative response to Mycobacterium tuberculosis antigens and the presence of gamma/delta TCR+ T cells employing several monoclonal antibodies. No consistent increase of gamma/delta TCR+ T cells was noted in inflammatory synovial fluids or tissues. Nonetheless, lymphocytes from the majority of the synovial fluids proliferated vigorously in response to water-soluble M. tuberculosis antigens. There was no relationship between the percentage of gamma/delta TCR+ T lymphocytes and the intensity of the proliferative response. In contrast, stimulation with whole mycobacterial organisms was capable of enriching the gamma/delta TCR+ cell population obtained from the peripheral blood of tuberculosis skin test positive normal controls and from some inflammatory synovial fluids. These observations do not support a role for mycobacteria reactive gamma/delta TCR+ synovial T lymphocytes in response to soluble mycobacterial antigens or in the local pathogenesis of inflammatory synovitis.     

Human T cell receptor-gamma and -delta chain pairing analyzed by transfection of a T cell receptor-delta negative mutant cell line

Specific TCR V gamma and V delta segments are found to be coordinately used on subpopulations of gamma delta T lymphocytes. The reasons for this phenomenon are unknown, but may include the inability of particular chains expressing unique V delta and V gamma segments to physically associate. V delta 2 is typically used together with V gamma 2 on human peripheral blood gamma delta T lymphocytes. To examine whether V delta 2 can be used in conjunction with distinct V gamma segments, a TCR- mutant of the human gamma delta T cell line MOLT-13, which expresses parental TCR gamma (V gamma 1.3) but not TCR-delta protein, was transfected with plasmids containing full-length TCR-delta cDNA using either V delta 2 or V delta 3. TCR reconstitution was successful in both transfectants and resulted in TCR protein and RNA levels similar to that of the parental MOLT-13 cell line. These cell lines could be activated through their receptors as assessed by increases in cytoplasmic free calcium. These studies imply that physical constraints cannot explain the observed chain pairing preferences. Other possible explanations are discussed.     

Modulation of gamma delta T cells in mouse buccal epithelium following antigen priming

T cells using the gamma delta T cell receptor (TCR) are abundant in mucosal and epidermal tissues in mice. Most studies of mucosal gamma delta T cells, however, have examined cells from the intestinal mucosa, whereas little is known about the presence or function of gamma delta T cells in the oral cavity. To better understand the involvement of oral gamma delta T cells in immunity, we have characterized TCR variable gamma-gene usage in the buccal epithelium from normal mice, and from mice challenged locally with a non-replicating antigen (bovine serum albumin [BSA]) or by influenza-virus infection as a replicating antigen. Our findings demonstrate a restricted use of V gamma genes by buccal gamma delta T cells, consisting primarily of V gamma 1.2, V gamma 3, and V gamma 5, with minimal use of V gamma 2 and V gamma 4 genes. Of particular interest, 3-4 days post-antigen challenge with BSA, there was a precipitous drop in the level of expression of V gamma 1.2, V gamma 3, and V gamma 5 genes, and to a lesser extent for the V gamma 2 gene, whereas V gamma 4 gene expression increased between days 1 and 2 post-priming. In influenza-infected mice, a similar pattern was observed for the V gamma 2 and V gamma 5 genes, but not other V gamma genes. The immune-modulating effects of oral antigen exposure on buccal gamma delta T cells suggest that these cells are functionally involved in the local immune response to both replicating and non-replicating antigens in oral mucosal surfaces.     

Avian T cells expressing gamma delta receptors localize in the splenic sinusoids and the intestinal epithelium

A panel of murine mAb specific for the chicken homologues of the CD3, CD4, CD8, TCR gamma delta, and TCR alpha beta has been used to study the distribution of T cells expressing these markers in sections of chicken lymphoid tissues. These studies have revealed that the T cells possessing the two classes of TCR occupy distinct histologic microenvironments. The TCR1+ cells (gamma delta TCR homologue) are localized preferentially in the splenic sinusoids and the intestinal epithelium, where most of them express the CD8 homologue. The TCR2+ cells (alpha beta TCR homologue), a majority of which express the CD4 homologue, are found primarily in the splenic periarteriolar sheath and the lamina propria of the intestine. The frequency and distribution of the two classes of T cells in the thymus is also unique. The different tissue homing patterns of the TCR1 and TCR2 cells suggest that they represent separate lineages of T cells with distinctive physiologic roles.     

The T cell receptors of human gamma delta T cells reactive to Mycobacterium tuberculosis are encoded by specific V genes but diverse V-J junctions.

The observation that gamma delta T lymphocytes react to mycobacteria has provided an important model for investigation of these cells in the immune response to infection. One important question regarding human gamma delta T cells is the breadth of the T cell repertoire in response to specific pathogens. The present study was undertaken to characterize, in molecular terms, the mycobacterium-specific gamma delta TCR repertoire. Mononuclear cells were isolated from the peripheral blood and pleural fluid of patients with tuberculous pleuritis and stimulated with Mycobacterium tuberculosis in vitro. Cytofluorometric analysis of the expressed gamma delta TCR repertoire of M. tuberculosis expanded cells was performed using anti-V region antibodies. The majority of responding gamma delta T cells express a receptor composed of V delta 2 and V gamma 9 chains. Molecular analysis by PCR amplification confirmed use of the V delta 2 and V gamma 9 gene segments in these cells, and demonstrated predominant usage of J delta 1 and J gamma P gene segments. Analysis of nucleotide sequence at the V-J junctions revealed extensive diversity including nucleotide deletions of V, D, and J gene segments and nucleotide segment additions. The predicted amino acid sequences further indicates diversity in the V-J encoded region of the protein chains. The data indicate that M. tuberculosis-driven expansion of gamma delta T cells in vitro depends on specific pairing of the V delta 2 and V gamma 9 polypeptide chains, without apparent selection of explicit V-J junction regions.     

Demonstration of a CD3+ lymphocyte subset in the epidermis of athymic nude mice. Evidence for T cell receptor diversity.

The existence of CD3/TCR-bearing lymphocytes in athymic and thymectomized chimeric mice implies that T cell maturation can occur in the absence of a thymus. Considering the possibility that the epidermis may be one of the organs providing T cell educating stimuli, we attempted to characterize the Thy-1+ epidermal lymphocyte population of athymic mice. Immunohistologic studies of epidermal sheets revealed (1) that Thy-1+ epidermal cells of C57BL/6 nu/nu mice are CD5-, CD4-, and predominantly CD8-, and (2) that a minor subset of these cells displays anti-CD3 epsilon reactivity. Although these CD3+ epidermal cells could hardly be detected at 6 wk of age, they comprised approximately 2% of all Thy-1+ epidermal cells in 12-mo-old athymic mice. Most of these CD3+ cells expressed TCR-gamma/delta, but TCR-alpha/beta+ cells were also present. TCR-gamma/delta+ epidermal T cells of athymic mice preferentially expressed TCR V gamma 2, V gamma 4, and V gamma 5 specificities rather than TCR V gamma 3 as found on DETC of euthymic mice. Using mitogenic stimuli, we have succeeded in establishing cell lines and clones from BALB/c nu/nu and C57BL/6 nu/nu epidermis. Their marker profile corresponds to that seen on resident CD3+ epidermal cells, as well as on a very small subset of CD3+ splenic and lymph node lymphocytes of athymic mice. The ontogenetic relationship, if any, between the epidermal and lymphoid CD3+, CD5-, CD4-, CD8- cells, has yet to be clarified. Cell lines/clones representative of resident CD3+ epidermal cells of nu/nu mice should provide a useful tool in the elucidation of homing patterns and functional properties of extrathymically matured T cells.     

Functional and morphologic characterization of human T lymphocytes expressing the TCR gamma /delta

A minor subset of T lymphocytes express a TCR composed of gamma and delta chains. This subset differs from conventional T cells for a number of phenotypic and functional characteristics. TCR gamma/delta+ cells simultaneously lack both CD4 and CD8 antigens. Cloning of CD4-8- peripheral blood lymphocytes, under limiting dilution conditions, revealed that they are homogeneously composed of cytolytic cells which efficiently lyse tumor target cells. Formal proofs have been provided that TCR gamma/delta+ cells are able to recognize antigens. For example, they proliferated in response to allogeneic mixed lymphocyte culture (MLC); in addition, MLC-derived TCR gamma/delta+ cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens. The selection of monoclonal antibodies specific for TCR gamma/delta molecules allowed to identify two distinct subsets of TCR gamma/delta+ cells. Both of these mABs, termed BB3 and delta TCS-1 respectively, induced specific activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca++ and/or lymphokine production or cytolytic activity). Analysis of the distribution of subsets expressing different forms of TCR gamma/delta, showed that the BB3-reactive form is prevalent in the peripheral blood. In contrast, delta-TCS-1-reactive cells are relatively unfrequent in peripheral blood but represent the majority of TCR gamma/delta+ cells in tissues.     

Extrathymic selection of TCR gamma delta + T cells by class II major histocompatibility complex molecules

The influence of MHC antigens on TCR gamma delta usage in CD8+ intraepithelial lymphocytes (IELs) was examined using a pan-reactive and V delta 4 region-specific MAb. While an average of 30% of IELs from the majority of mice of various MHC haplotypes were V delta 4+, a 2-fold or greater percentage of IELs from H-2k mice were V delta 4+. Analysis of IELs from F1 mice indicated that the increase in TCRs using V delta 4 was likely to be the result of positive selection. The V delta 4 usage patterns of IELs from recombinant inbred strains and from mice recombinant within H-2 revealed that the increase in V delta 4 usage mapped to H-2 and required I-E expression. Moreover, selection of TCRs using V delta 4 occurred in chimeric mice in the absence of a thymus. The results demonstrate an extrathymic selective mechanism for gamma delta TCRs of CD8+ IELs and suggest that these cells may exhibit MHC class II-restricted antigen recognition.     

gamma delta T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium

We have investigated the expression of the alpha beta and the gamma delta T cell receptor (TCR) in the human intestine. By immunohistology we found that 39% of CD3+ intraepithelial lymphocytes (IEL) expressed the gamma delta TCR compared to 3% of CD3+ lamina propria lymphocytes (LPL). Cytofluorometric analysis of isolated cells revealed a significantly higher proportion of gamma delta T cells among CD3+ IEL compared to LPL and peripheral blood lymphocytes. This was due to an increase in both CD8+ (low density) and CD4-CD8- gamma delta T cells in IEL. Most alpha beta IEL expressed high-density CD8. About 30% of both IEL and LPL expressed CD25 (alpha-chain of the IL-2 receptor). HML-1 expression was detected on nearly all IEL and on 27% of LPL. CD25 and HML-1 were preferentially expressed on intestinal alpha beta and gamma delta T cells, respectively. Thus, human gamma delta T cells are located preferentially in the gut epithelium and are phenotypically different from alpha beta T cells, which constitute the majority of both LPL and IEL.     

Early appearing gamma/delta-bearing T cells during infection with Calmétte Guérin bacillus.

To search for a potential role of TCR gamma/delta T cells in host-defense against mycobacterial infection, we analyzed the kinetics, repertoire, specificity, and cytokine production of gamma/delta T cells in the peritoneal exudate cells (PEC), lymph node (LN) cells and spleen cells during an i.p. infection with a sublethal dose (5 x 10(5) of viable Bacillus Calmétte-Guérin (BCG) in mice. In the PEC on day 7 after infection, approximately 26% of the CD3+ cells were CD4-CD8-, most of which expressed TCR gamma/delta on their surface. However, the PEC on day 28 contained an increased number of alpha/beta T cells that were CD4+8- or CD4-8+ and the proportion of gamma/delta T cells in the PEC reciprocally decreased to 18% of the CD3+ cells. The kinetics of gamma/delta and alpha/beta T cells in the LN during BCG infection showed in much the same pattern as that seen in the PEC. When purified CD4-CD8- cells in the LN on day 7 after BCG infection were cultured with sonicated BCG lysate, PPD derived from Mycobacterium tuberculosis or recombinant 65 kDa heat shock protein derived from Mycobacterium bovis, the gamma/delta T cells on this stage significantly proliferated and secreted IL-2 in response to sonicated BCG lysate and PPD but not to 65 kDa heat shock protein. V gene segment usage analysis with PCR method revealed that purified protein derivative-reactive gamma/delta T cells preferentially used V gamma 1/2/V delta 6, whereas gamma/delta T cells polyclonally expanded in response to the BCG lysate. These results suggest that gamma/delta T cells specific for mycobacterial antigens preceding alpha/beta T cells in appearance during infection may serve as a first line of defense against mycobacterial infection.     

Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues

Frozen sections from normal and pathologic human tissues were immunostained by the APAAP technique with three mAb directed against different epitopes of the TCR gamma delta; TCR delta 1 which binds to all cells bearing the TCR gamma delta; BB3 and delta TCS1 which, by immunoprecipitation studies, appear to react respectively with the disulfide-linked and nondisulfide-linked form of the TCR gamma delta. In normal thymus, TCR delta 1+ cells accounted for approximately 2% of the CD3+ thymocytes and were about three times more numerous in the medulla than in the cortex. TCR delta 1+ cells were mostly constituted by the delta TCS1 reactive subset (average ratio delta TCS1/BB3: 3.7). In the tonsil, the TCR delta 1+ cells (about 3% of CD3+ elements) were mainly located in the interfollicular area, where they frequently tended to arrange around high endothelium venules. In most samples, TCR delta 1+ cells were distributed beneath to the tonsil epithelium. Unlike thymus, the majority of TCR delta 1+ cells were usually constituted by the BB3-reactive subset (average BB3/delta TCS1 ratio: 2.0). A similar predominance of BB3+ over delta TCS1+ cells was also observed in normal peripheral blood. The spleen was the organ with the highest concentration of TCR delta 1+ cells that, like in the thymus, were mostly represented by delta TCS1+ elements. Noteworthy, the TCR delta 1+ cells were preferentially located in the splenic sinusoids while TCR alpha beta-bearing lymphocytes mostly occupied the periarteriolar sheaths of penicilliary arteries. The majority of neoplastic T cell proliferations studied lacked to express the TCR gamma delta. Two cases of beta F1-(TCR alpha beta-) T lymphoblastic lymphoma, however, were TCR gamma delta+ (delta TCS1+/BB3-). Both of them showed a stage II cortical phenotype, e.g., CD1+/CD3+/CD4+/CD8+/TCR delta 1+. Among inflammatory conditions, an increase of BB3+ cells was observed in close association with necrotic areas in cases of Kikuchi's and tuberculous lymphadenitis. The significance of this finding is under study.     

Different roles of the CD2 and LFA-1 T-cell co-receptors for regulating cytotoxic, proliferative, and cytokine responses of human V gamma 9/V delta 2 T cells

BACKGROUND: Human V gamma 9/V delta 2 T lymphocytes recognize nonpeptidic antigens in a manner distinct from the classical antigen recognition by alpha beta T cells. The apparent lack of major histocompatibility (MHC) restriction and antigen processing allows very fast responses against pathogenic insults. To address the potential functional requirement for accessory molecules, we investigated the roles of the CD2 and lymphocyte function-associated antigen (LFA)-1 T-cell co-receptors in antigen-induced activities of human V gamma 9/V delta 2 T-cell clones. MATERIALS AND METHODS: Human peripheral blood V gamma 9/V delta 2 T lymphocytes were cloned and their cytotoxicity against Daudi lymphoma was measured by a standard 51Cr-release assay. The responses of V gamma 9/V delta 2 T lymphocytes to nonpeptidic antigens were assessed using DNA synthesis and cytokine ELISA assays. Monoclonal antibodies specific for various molecules with potential T-cell accessory functions were utilized in blocking assays. RESULTS: All of our V gamma 9/V delta 2 T-cell clones displayed the Th1 phenotype. The anti-LFA-1 antibody strongly inhibited the cytotoxicity of V gamma 9/V delta 2 T cells against Daudi B-cell lymphoma; whereas, it had no influence on the antigen-induced cytokine release or proliferation. In contrast, antibodies against CD2 and LFA-3 had no effect on the lytic activity of V gamma 9/V delta 2 T cells, but strongly inhibited the cytokine release and proliferation. However, the CD2-LFA-3 interaction was not an absolute requirement for the cytokine release and the DNA synthetic activity of antigen-stimulated V gamma 9/V delta 2 T cells, since the inhibitory effect could be reversed by addition of exogenous interleukin 2 (IL-2). CONCLUSIONS: These novel observations indicate that the signals generated by different accessory molecules and IL-2 can contribute in an integrated fashion to the regulation of V gamma 9/V delta 2 T cells. These interactions may be important for the effectiveness of V gamma 9/V delta 2 T-cell responses.     

Unusual alpha beta-T cells expanded in autoimmune lpr mice are probably a counterpart of normal T cells in the liver.

Autoimmune MRL-lpr/lpr (lpr) mice develop severe lymphadenopathy, characterized by the accumulation of alpha beta-T cells with CD4-8- double negative (DN) phenotype, at the onset of disease. We previously demonstrated that the liver is a major site for the proliferation of such DN alpha beta-T cells. Herein, we further demonstrate that a large proportion of alpha beta-T cells in the liver and other organs, except the thymus, of lpr mice have unique properties, such as DN phenotype, relatively dull TCR intensity, a preponderance of V beta 8+ cells, and Pgp-1 expression. Interestingly, alpha beta-T cells in the liver of normal mice were found to consist of T cells with intermediate intensity of TCR (i.e., brighter than thymic dull TCR and lower than thymic bright TCR) as well as with bright intensity of TCR in the immunofluorescence test. These hepatic alpha beta-T cells with intermediate TCR in normal mice were found to have properties similar to those of alpha beta-T cells in lpr mice. These results suggest that abnormal alpha beta-T cells in lpr mice are a counterpart of normal T cells in the liver. An abnormal expansion of such T cells in the liver might be fundamental to the pathogenesis involved in these autoimmune mice.