Sequential Analysis of Distributions of Donor-derived Thymocytes Bearing T-cell Antigen Receptor (TCR) and Donor-derived la+ Cells in Thymuses of Fully Allogeneic Bone Marrow Chimera in Mice

Lethally irradiated SJL/J mice were reconstituted with B10 bone marrow cells, and the process of thymic reconstitution by donor derived cells positive for I- A or Vβ8 molecules was investigated. The donor-derived la⁺ cells appeared in the medulla on day 7 after reconstitution. The la+ cells became confluent up to day 14, and the cellularity in the medulla on day 17 was almost the same as that in the normal thymus. Dull Vβ8⁺ thymocytes were first recognized in the cortex on day 10 and were identifiable in the medulla by day 14. The Vβ8⁺ cells seemed to be mainly CD4⁺8⁺ double-positive. Furthermore, most of the Vg8'cells in the medulla of chimeras given cyclosporin A for 3 weeks after reconstitution appeared to be CD4⁺8⁺. The present findings demonstrate that CD4 8+ thymocytes which bear a low concentration of TCR exist in the thymic medulla at a relatively early stage when donor-derived la⁺ cells have already settled there. The coincidental appearance and coexistence of la⁺ cells and TCR⁺ thymocytes in the medulla suggest that these histological characteristics may be related to the selection of thymocytes in this area.     

Lineage commitment and differentiation of T and natural killer lymphocytes in the fetal mouse

Summary: T cells and natural killer (NK) cells are presumed to share a common intrathymic precursor. The development of conventional a|3 T lymphocytes begins within the early fetal thymus, after the colonization of multipotent CDl1 71 precursors. Irrevocable commitment to the T lineage is marked by thymus-induced expression of CD25. However, the contribution of the fetal thymus to NK lineage commitment and differentiation remains largely unappreciated. Recently, we demonstrated that the development of functional mouse NK cells occurs first in the fetal thymus. Moreover, the appearance of mature fetal thymic NK cells (NK1.1⁺/CD 117^-) is preceded by a thymus-induced developmental stage (NKl.1⁺/CD1 17⁺) that marks lineage commitment of multipotent hematopoietic precursors to the T and NK-cell fates. Commitment to the T/NK bipotent stage is induced by fetal thymic stroma, but is not thymus dependent. Recent data indicate that CD90⁺/CD117^lo fetal blood prothymocytes exhibit NK lineage potential and are phenotypically and functionally identical to fetal thymic NK1,1⁺/CD1 17⁺ progenitors. This finding also indicates that full commitment of circulating precursors to the T-cell lineage occurs after thymus colonization. In this review, we discuss recent insights into the cellular and molecular events involved in fetal mouse T and NK lineage commitment and differentiation to unipotent progenitors.     

Macrophage Populations in Different Stages of Induced Hepatic Metastases in Rats: an Immunohistochemical Analysis

Macrophages play a role in the host defence against cancer. Little is known about changes in macrophage populations during early metastatic growth. To evaluate the distribution, number and phenotype of macrophages in the development of hepatic metastases in a rat model (Wag/Rij rats and syngeneic CC531 colon carcinoma cell line), an immunohistochemical study was performed with the monoclonal antibodies ED1 (monocytes, and all macrophages), ED2 (resident tissue macrophages, like Kupffer cells) and ED3 (a subpopulation of macrophages which may play a role in the recruitment of lymphocytes). OX19 and Hisl4 were used to identify lymphocytes. In this study a new monoclonal antibody CC52 is described, which recognizes the CC531 tumour cell line. Liver metastases were induced by injection of CC53I colon carcinoma cells into a mesenteric vein. Rats were killed at various intervals. Results show three major macrophage populations during hepatic tumour growth: (1) on day 3, infiltrates are observed around the micrometastases, which contain mainly newly recruited macrophages (ED1⁺ and ED2⁻); (2) after 7 days, ED3-positive (ED3 ⁺) macrophages together with T lymphocytes are found in the infiltrates; (3) an increase in the number of ED2-positive (ED2⁺) Kupffer cells is observed in the liver parenchyma after 14 days. In conclusion, the present results suggest that various populations of macrophages, newly recruited (ED1⁺) as well as resident Kupffer cells (ED2⁺), are involved in the immune response against tumour cell deposits in the liver.     

T-ZONE HISTIOCYTES WITH S100 PROTEIN

Histiocytic cells with S100 protein compose a cell lineage independent of the monocyte-macrophage system. Langerhans cells and indeterminate cells in the skin and oral mucosa, interdigitating cells in the T-zone of the lymph node, and other lymphoid tissues belong to this cell lineage. In addition to these cells, small S100⁺ cells showed morphological transition to large histiocytes. In human fetuses, a large number of S100⁺ lysozyme^- NCA⁺ cells first appeared in the thymic medulla by the end of the third month of gestation, and rapidly disseminated to the various lymphoid organs in accordance with the spread of T-lymphocytes during the fourth month of gestation. S100+ small cells were more frequent than large cells and showed more rapid dissemination in the early stage. S100- lysozyme⁺ NGA⁺ immature macrophages appeared in the liver, spleen, lymph node anlage, and other tissues at the second month of gestation, and their distribution was completely different from S100⁺ histiocytes. Fetal development of T-zone histiocytes with S100 protein supported the hypothesis that there are two histiocytic cell lines; one is the monocyte-macrophage system, another is the S100⁺ T-zone histiocyte system.     

Interleukin-2 and Serum Thymic Factor Enable Autologous Rosette-forming T Lymphocytes to Generate Helper and Cytotoxic Functions

The autologous rosette-forming T cells (Tar cells) isolated by means of their ability to form rosettes with autologous erythrocytes were characterized by the use of OKT monoclonal anti-human T-cell subset antibodies and a monoclonal anti-HLA-DR antibody. We found that the phenotype of Tar cells was OKT 3⁺4⁺8⁺Dr⁻ as determined by both indirect imnrunofluorescence microscopy and complement-mediated killing of ⁵¹Cr-labelled Tar cells. In addition, we found that Tar lymphocytes were able to develop cytotoxicity against allogeneic and trinitrophenol (TNP)-conjugated autologous target cells in the presence of interleukin-2 (IL-2) or serum thymic factor. However, these cells showed little or no cytotoxicity in the absence of interleukin-2 or serum thymic factor. Tar lymphocytes generated helper function for B lymphocytes in the presence of interleukin-2 in both pokeweed mitogen (PWM)- and purified protein derivative (PPD)-stimulated cultures. Nevertheless, non-IL-2-treated Tar cells did not exhibit any helper activity on B cells. Finally, pretreatment of Tar cells with 1000–1500 rad of X ray made these cells unable to develop helper function for B lymphocytes. It is concluded that: (1) OKT 3⁺4⁺8⁺Dr⁻ Tar cells are able to generate cytotoxicity against alloantigens and TNP-labelled self structures provided they are stimulated by IL-2 or serum thymic factor; (2) these cells need both to proliferate and to receive help from IL-2 to develop helper cells capable of assisting B-lymphocyte differentiation into plasma cells in both PWM- and PPD-stimulated cultures.     

Phenotypic Characterization of Macrophages in the Endometrium of the Pregnant Cow

Problem  Macrophages are recruited in large number to the interplacentomal endometrium of the cow during pregnancy. We evaluated whether endometrial macrophages also accumulate in placentomal regions of endometrium during pregnancy and whether endometrial macrophages are regionally differentiated.
Method of study  Interplacentomal endometrium and placentomes were subjected to dual-color immunofluorescence using CD68 as a pan-macrophage marker.
Results  CD68⁺ cells were abundant in stroma of the interplacentomal endometrium and caruncular septa of the placentomes. CD68⁺ cells were not present in fetal villi of the placentomes or in the interplacentomal chorion. Regardless of location, the majority of CD68⁺ cells also expressed CD14. In interplacentomal endometrium, CD68⁺CD11b⁺ cells were present in deeper areas of the stroma but not in shallow endometrial stroma. In caruncular septa of the placentome, CD68⁺ cells were negative for CD11b. CD68⁺ cells in the interplacentomal endometrium were negative for MHC class II while most CD68⁺ cells in caruncular septa were positive for MHC class II.
Conclusion  CD68⁺CD14⁺ macrophages present in the stroma of the interplacentomal endometrium and caruncular septa of the placentome are regionally differentiated with regard to expression of CD11b and MHC class II.     

CD3−4−8− Thymocyte Precursors with Interleukin-2 Receptors Differentiate Phenotypically in Coculture with Thymic Stromal Cells

CD3⁻4⁻8⁻ interleukin-2 receptor positive (IL-2R⁺) thymocyte precursors from adult mice were cocultured with thymic stromal cells from syngeneic adult mice. The IL-2R⁺CD3⁻4⁻8⁻ thymocytes were obtained by positive panning of IL-2R⁺ cells followed by either sorting or negative panning of triple negative cells, and they were cocultured with primary or secondary cultures of heterogeneous thymic stromal cells. Phenotypic maturation of these precursor cells was extremely rapid. Within 2½ days significant numbers of CD4⁺8⁺ and CD3⁺4⁺8⁻ cell populations developed, the latter expressing the αβ T-cell receptor (αβ-TCR). Thus heterogeneous stromal cell cultures support the development of IL-2R⁺ precursors and with these methods it will now be possible to isolate the particular stromal cells involved at each stromal-dependent step.     

Population Dynamics of CD4+ T Cells Lacking Thy-1 in Murine Retrovirus-Induced Immunodeficiency Syndrome (MAIDS)

Increased numbers of CD4⁺ Thy-1 cells have been described in the spleen (SP) of mice with retrovirusinduced immunodeliciency (MAIDS). Since this phenotypic abnormality might have considerable functional importance, the expansion of the CD4⁺ Thy-1 subset in MAIDS was characterized further. CD4⁺ Thy-1⁻ and Thy-1⁺ T-cell is from infected mice expressed similar densities of CD3 and TCR γ/β. In contrast, the Thy-I⁻ subset was uniformly CD44^hi, even early in the disease when part of Thy-I⁺ cells were still CD44¹⁰. The emergence of CD4⁺ Thy-1⁻cells occurred first in SP and lymph nodes and was observed later in thymus. The important fraction ofCD4⁺ cells lacking Thy-1 normally present in Peyer's patches was only weakly modified. Despite the major expansion of the CD4⁺ Thy-1⁻ phenotype. the proliferating fraction was not higher in this subset than in CD4⁺ Thy-1⁺ cells from infeeted miee. Persistence after hydroxyurea administration was identical in both subsets, indicating similar mean cell lifespans. Taken together, these results show that the major expansion of CD4⁺ Thy-I⁻ T-cells in MAIDS is not ascribable solely to increased proliferation within this subset. Phenotypic analysis suggests that CD4⁺ Thy-I⁻ cells result from the differentiation of Thy-I⁺ cells induced by activation signals related to retroviral infection.     

Characterization of T-Lymphocyte Colony-Forming Cells in the Mouse

T-cell colony-forming cells (CFC), the cells from which T-lymphocyte colonies are initiated when cells are grown in semisolid medium, have been studied. CFC have previously been shown to be more frequent in populations of rather mature thymic cells and peripheral lymphocytes than in populations of immature cortical thymocytes. We have here evaluated whether CFC in spleen and lymph nodes are confined either to newly emigrated thymocytes or to older recirculating T cells, h is shown that CFC in spleen have the same Lyt phenotype as thymic and lymph node CFC, namely Lyt-1⁺ 2⁺, and that the peripheral complement of CFC is rather slowly built up after birth or after total body irradiation and bone marrow reconstitution. Results obtained after fluorescence-activated cell sorting, hydrocortisone injection, or thymectomy indicate that CFC are present in a broad variety of peripheral T-cell populations in accordance with age and thus that T-cell colonies can be used to lest the proliferate capacity of the 'average' peripheral T cells of the Lyt-1⁺2⁺ phenotype.     

Control of intestinal inflammation by regulatory T cells

Summary: Transfer of CD4⁺ T cells to immune-deficient mice in the absence of the CD25⁺ subset leads to the development of colitis, indicating that regulatory cells capable of controlling a bacteria-driven inflammatory response are present in normal mice. Cells with this function are present in the thymus as well as in the periphery of germ-free mice, suggesting they may be reactive with self-antigen. These cells resemble CD4⁺CD25⁺ cells that inhibit organ-specific autoimmunity, suggesting that a similar subset of regulatory T cells may control responses to self and foreign antigens. Development of colitis is dependent on accumulation of activated CD134L⁺ dendritic cells (DC) in the mesenteric lymph nodes, which is inhibited by CD4⁺CD25⁺ cells, indicating that regulatory T cells may control DC activation in vivo . Whilst inhibition of T-cell activation in vitro by CD4⁺CD25⁺ cells does not involve interleukin-10 and transforming growth factor-β, these cytokines are required for the suppression of colitis. It may be that control of responses that activate the innate immune system requires multiple mechanisms of immune suppression. Recently, we identified CD4⁺CD25⁺ cells with immune suppressive activity in the thymus and peripheral blood of humans, raising the possibility that dysfunction in this mechanism of immune regulation may be involved in the development of autoimmune and inflammatory diseases.     

STUDIES ON LYMPHOCYTE SUBSETS IN THYMIC TISSUE AND FUNCTIONS OF PERIPHERAL LYMPHOCYTES IN PATIENTS WITH TUMOROUS THYMUS WITH SPECIAL REFERENCE TO MYASTHENIA GRAVIS

In order to obtain a better understanding of the immunological abnormalities present in myasthenia gravis (MG), which is often accompanied by thymoma or thymic hyperplasia, we investigated lymphocyte subsests and their functions using samples of thymoma or thymic hyperplasia tissues from 11 patients (6 cases with MG), and peripheral blood from 6 patients (4 cases with MG). In most thymic tissues from patients with MG, a maturating tendency of lymphocytes was generally observed. Especially in the medulla of thymic hyperplasia, an entirely peripheral blood type of T-lymphocytes, which were Leu-6⁻ and either Leu-2a⁺ or 3a + 3b⁺, were encountered abundantly. Therefore, the presence of abnormal maturation of lymphocytes in the thymus or destruction of the barrier between the thymus and the peripheral blood in MG cases was indicated. In cases without MG, no such tendency was noted. As to the peripheral blood in patients with MG, concanavalin A-induced suppressor cells were significantly decreased (p<0.01). All of these changes were considered to be intimately related to the appearance of MG.     

The CD4+CD8+ and CD4+ Subsets of FOXP3+ Thymocytes Differ in their Response to Growth Factor Deprivation or Stimulation

The timing of thymic regulatory T (Treg) cell commitment remains unclear. Specifically, there is disagreement as to whether the CD4⁺CD8⁺ FOXP3⁺ thymocytes are precursors of mature CD4⁺ FOXP3⁺ Treg cells, or an independent Treg cell lineage. We reasoned that precursors should be more susceptible to apoptosis than mature Treg cells, and tested this by growth factor removal and anti-CD3 stimulation. Both treatments resulted in an increase of CD4⁺ FOXP3⁺ thymocytes, whereas the frequency of CD4⁺CD8⁺ FOXP3⁺ thymocytes decreased significantly. These changes were accompanied by an increase of annexin⁺ apoptotic cells. Both of these FOXP3⁺ subsets expressed higher levels of Bcl-2 and BIM than other thymocytes, and while in our setting expression of BIM seemed to predispose the cells to apoptosis, Bcl-2 had no apparent protective effect. These results indicate that CD4⁺CD8⁺ FOXP3⁺ thymocytes are more susceptible to apoptosis than mature CD4⁺ FOXP3⁺ Treg cells. This is consistent with the view that they are still immature and thus likely to represent a precursor population.     

3, 3', 4, 4'-Tetrachlorobiphenyl Inhibits Proliferation of Immature Thymocytes in Fetal Thymus Organ Culture

The environmental pollutant 3, 3', 4, 4'-tetrachlorobiphenyl (TCB) leads to thymic atrophy and immuno-suppression, the former possibly causing the latter. TCB binds lo the cytosolic aryl-hydrocarbon receptor (AhR) and transforms it into a DNA-binding state. The development of fetal thymocyles is severely affected by TCB and other AhR-binding xenobiotics, leading to a skewed pattern of thymocyte maturation stages. Murine thymocyte proliferation after exposure to TCB was studied in fetal thymus organ culture (FTOC). C57BL/6 fetus thymic lobes from day 15 of gestation were explanted and grown for 2, 4, 6. and 8 days in organ culture in the presence or absence of 3.3 μM TCB. Subsets of thymocytes were defined by CD4 and CD8 surface markers, and their cell cycle was analysed by DNA staining with 7-amino-actinomycin D (7-AAD). Exposure of fetal thymi in vitro to 3.3 μM TCB significantly reduced the total number of thymocytes. and fewer thymocytes were in S/G₂M phase. The inhibition of cell proliferation induced by TCB treatment affected mainly the CD4⁻ CD8⁻ (double-negative, DN) and CD4⁻ CD8⁺ (single-positive, SP) subsets, and these inhibition appeared mainly in more immature thymocytes, i. e. DNCD3⁻ and CD8⁺CD3⁻ subpopulations, whereas no effect of TCB on CD4⁺CD8⁺ (double-positive, DP) cell proliferative activity was observed. Analysis of the relation of cell proliferation and development of subsets in differentiating fetal ihymocytes suggests that TCB enhanced thymocyte differentiation into mature CD8⁺ cells.     

An unbiased stereological study on subpopulations of rat liver macrophages and on their numerical relation with the hepatocytes and stellate cells

Studies on liver macrophages have elucidated their key roles in immunological, fibrotic and regenerative responses, and shown that macrophages are not a homogeneous population. In the rat, two sets of liver macrophages coexist, identified by ED1 and ED2 antibodies. Those sets have different quantitative responses in liver injuries and may have different tasks throughout the injury and recovery phases. Nevertheless, the total number (N), number per gram (N g⁻¹) and proportion of those macrophages in relation to other liver cells has never been quantified using design-based stereology. Thus, we combined immunocytochemistry with those tools to produce an unbiased estimate of the N of ED1⁺ and of ED2⁺ cells. A smooth fractionator sampling scheme was applied to the liver of five male Wistar rats (3 months old), to obtain systematic uniform random sections (30 µm thick); these were immunostained with the monoclonal antibodies: ED1, a pan-macrophagic marker; and ED2, which identifies the completely differentiated macrophages, i.e. Kupffer cells. The N of ED1⁺ cells was 340 × 10⁶, estimated with a coefficient of error (CE) of 0.04, and that of ED2⁺ cells was 283 × 10⁶, with a CE of 0.05. These figures correspond to 10.7% and 8.9%, respectively, of the total liver cells. The new data constitute reference values for correlative inferences. Also, the methodological strategy, by its accuracy and precision, is valuable for future investigations on the liver cell composition in various models of disease, and especially for studying the more subtle variations that occur during the injury and recovery phases.     

Allergen-Induced Migration of Human Cells in Allergic Severe Combined Immunodeficiency Mice

Recently, we have shown that severe combined immunodeficiency (SCID) mice, intraperitoneally reconstituted with peripheral blood mononuclear cells (PBMC) from Dermatophagoides pteronyssinus ( Dpt )-sensitive patients, produced human IgE and developed a pulmonary inflammatory-type reaction after exposure to allergen aerosol. In order to understand the potential mechanisms involved in the human cell migration in SCID mice, we analysed their phenotypic profile in the lungs, spleen and thymus, 2 months after Dpt inhalation. The human cell recruitment in these organs was found to be allergen-dependent as CD45⁺ human cells were only detected in hu-SCID mice after Dpt exposure. The composition of the pulmonary human T-cell infiltrate, preferentially memory (CD45RO), activated (human leucocyte antigen (HLA)-DR) and CD4⁺ cells, was similar to that described in asthmatic patients. However, CD20⁺ B cells were predominately recruited in the spleen and thymus and may be IgE-producing cells in the spleen. In the lungs, the percentage of human leucocytes expressing the α-chain of the lymphocyte function-assiciated antigen-1 (LFA-1) (CD11a) was higher than those of CD49d⁺ or CD54⁺ cells, in contrast to the spleen and thymus, suggesting a potential role of LFA-1 in the human cell migration towards SCID mice lung. In conclusion, this model could be useful in the study of factors implicated in the cellular migration towards the lymphoid organs during an allergic reaction.     

Induction of Apoptosis and p53 Expression in Immature Thymocytes by Direct Interaction with Thymic Epithelial Cells

Apoptosis of normal thymocytes was shown to be triggered by several mechanisms (e.g. glucocorticoids, γ-irradiation). In the present study the authors report on thymocyte apoptosis that is induced by thymic epithelial cells. The thymocytes undergo a massive apoptotic death within 24 h of cocultivation with thymic epithelial cell monolayers derived from primary cultures (PTEC) or from a thymic epithelial cell line (TEC). Non-thymic monolayers were inactive. Apoptosis induction in this experimental model requires direct contact between the thymocytes and the thymic epithelial monolayer and can be blocked by anti-CD2 and anti-LFA-1 antibodies. The immature CD3^−/+dull CD4⁺CD8⁺ thymocytes were the cells which undergo apoptosis. The fact that the authors are dealing with a massive apoptotic process of immature cells in the absence of exogenous antigen suggests that it involves the nonselected thymocytes. The apoptotic pathway selected by thymocytes following their culturing on TEC involves p53 expression. Indeed it was found that TEC-induced apoptosis, led to the accumulation of p53 protein that preceded the step of DNA fragmentation in freshly isolated thymocytes as well as in a glucocorticoid resistant thymoma cell line. Since glucocorticoid-induced thymocyte apoptosis is p53-independent, glucocorticoids are conceivably not involved in TEC-induced thymocyte death. The in vitro experimental model presented here may reflect the physiological sequence of events leading to thymocyte death in the thymus.     

Proliferation Kinetics of Rat Kupffer Cells after Partial Hepatectomy Immunohistochemical and UItrastructural Analysis

In an effort to settle the conflicting views on the proliferation kinetics of Kupffer cells (Kc), we performed 2/3 partial hepatectomy on rats injected with Pelikan ink. Using an anti-rat macrophage monoclonal antibody, ED 2, we evaluated the numerical changes in total, carbon-positive ED 2⁺ cells and carbon-negative ED 2⁺ cells in the portal and central area. We also analyzed the ultrastructure and peroxidase cytochemistry of various types of cells observed during regeneration. The total numbers of ED 2⁺ cells in the remaining liver increased rapidly from day 2 to 5, and the number of dividing ED 2⁺ cells reached a maximum on day 2. Thus, the numerical increase in ED 2⁺ cells corresponded to the division phase. In contrast, the carbon-labeling experiment showed a continuous increase of carbon negative ED 2⁺ cells from day 2 to 7. In the central area where division was less frequent, the proportion of carbon-positive cells decreased markedly to 50% on day 7, as against 97% in control rats. These findings suggest the possibility of an influx of carbon-negative Kc in addition to cell division. Ultrastructurally, the presence of carbon-negative "small Kc" and "immature Kc" with morphological features different from those of carbon-positive Kc was demonstrated. Such carbon-negative Kc with a high nucleus-to-cytoplasm ratio and rather few phagosomes, were not observed in control rats. Furthermore, we demonstrated two types of possible precursor cell, i.e. "transitional" forms between monocytes and Kc, and "immature macrophages". The former showed peroxidase activity in some lysosomes as well as in the rough endoplasmic reticulum and nuclear envelope. Our result indicated that the proliferation kinetics of Kc depend upon both local proliferation and influx.     

Thymic differentiation of TCRαβ+ CD8αα+ IELs

Summary:  Intraepithelial lymphocytes (IELs) contain several subsets, but the origin of the T-cell receptor (TCR)αβ⁺ CD8αα⁺ IELs has been particularly controversial. Here we provide a synthesis, based on recent work, that attempts to unify the divergent views. The intestine has a primordial function in lymphopoiesis, and precursors with the potential to differentiate into T cells are found both in the epithelium and underlying lamina propria. Moreover, the thymus has been reported to export cells to the intestine that are not fully differentiated. TCRαβ⁺ CD8αα⁺ IELs can differentiate in the intestine from each of these sources, but in normal euthymic mice, the thymus appears to be the major source for TCRαβ⁺ CD8αα⁺ IELs. This unique IEL subset is a self-reactive population that requires exposure to self-agonists for selection in the thymus, similar to other regulatory T-cell populations. IELs transition through a double-positive (DP) intermediate in the thymus, but they originate from a subset of the DP cells that can be identified by its expression of CD8αα homodimers. The agonist-selected cells in the thymus are TCRβ⁺ but CD4 and CD8 double negative. The evidence suggests that reacquired expression of CD8αα and downregulation of CD5 occur after thymus export, perhaps in the intestine under the influence of interleukin-15. As a result of agonist exposure, a new gene expression program is activated. Therefore, the increased understanding of the developmental origin of TCRαβ⁺ CD8αα⁺ IELs may help us to understand how they participate in immune regulation and protection in the intestine.     

Immune privilege in sites of chronic infection: Leishmania and regulatory T cells

Summary:  Leishmania are digenetic protozoan parasites that are inoculated into the skin by vector sand flies, are taken up by macrophages, and produce a spectrum of chronic diseases in their natural reservoir and susceptible human hosts. During the early establishment of infection in the skin and lymphoid organs, Leishmania produce multiple effects on macrophage and dendritic cell functions that inhibit their innate anti-microbial defenses and impair their capacity to initiate T-helper 1 cell immunity. In addition, the skin is a site preconditioned for early parasite survival by virtue of a high frequency of steady-state, natural CD25⁺Foxp3⁺ regulatory T cells (Tregs) that function to suppress the generation of unneeded immune responses to infectious and non-infectious antigens to which the skin is regularly exposed. In murine models of infection, antigen-induced CD25^+/−Foxp3⁻interleukin (IL)-10⁺ Treg cells act during the effector phase of the immune response to control immunopathology and may also delay or prevent healing. Finally, following resolution of infection in healed mice, CD25⁺Foxp3⁺ Tregs function in an IL-10-dependent manner to prevent sterile cure and establish a long-term state of functional immune privilege in the skin.