The role of antigenic peptide in CD4+ T helper phenotype development in a T cell receptor transgenic model

CD4+ Th1 cells play a critical role in the induction of cell-mediated immune responses that are important for the eradication of intracellular pathogens. Peptide-25 is the major Th1 epitope for Ag85B of Mycobacterium tuberculosis and is immunogenic in I-Ab mice. To elucidate the role of the TCR and IFN-gamma/IL-12 signals in Th1 induction, we generated TCR transgenic mice (P25 TCR-Tg) expressing TCR alpha- and beta-chains of Peptide-25-reactive cloned T cells and analyzed Th1 development of CD4+ T cells from P25 TCR-Tg. Naive CD4+ T cells from P25 TCR-Tg differentiate into both Th1 and Th2 cells upon stimulation with anti-CD3. Naive CD4+ T cells from P25 TCR-Tg preferentially develop Th1 cells upon Peptide-25 stimulation in the presence of I-Ab splenic antigen-presenting cells under neutral conditions. In contrast, a mutant of Peptide-25 can induce solely Th2 differentiation. Peptide-25-induced Th1 differentiation is observed even in the presence of anti-IFN-gamma and anti-IL-12. Furthermore, naive CD4+ T cells from STAT1 deficient P25 TCR-Tg also differentiate into Th1 cells upon Peptide-25 stimulation. Moreover, Peptide-25-loaded I-Ab-transfected Chinese hamster ovary cells induce Th1 differentiation of naive CD4+ T cells from P25 TCR-Tg in the absence of IFN-gamma or IL-12. These results imply that interaction between Peptide-25/I-Ab and TCR may primarily influence determination of the fate of naive CD4+ T cells in their differentiation towards the Th1 subset.     

Characterization of Subpopulations of T-Cell Receptor Intermediate (TCRint) T Cells

CD1-autoreactive T cells of two types have been demonstrated among T cells expressing the T-cell receptor (TCR) alphabeta at intermediate levels (TCRint cells). One type constitutes a major fraction of the natural killer (NK)1.1+ TCRint population in C57BL/6 (B6) mice and carries a restricted TCR composed of an alpha-chain with an invariant Valpha14-J281 rearrangement, and a beta-chain using Vbeta8. 2, 7 or 2. The second type utilises a variety of TCR and was derived from CD4+ cells in mice lacking MHC class II. To increase our understanding of the two different CD1-reactive subsets, we have investigated and compared the populations of origin: NK1.1+ and NK1. 1- TCRint subsets from MHC class II-deficient mice and CD4+NK1.1+ T cells from B6 mice. The three TCRint populations shared a phenotype indicating previous activation, and contained low frequencies of cells expressing NK receptors of the Ly49 family. In contrast to control CD4+ cells, the three TCRint subsets produced high amounts of interleukin (IL)-4 and interferon (IFN)-gamma after activation. Importantly, no IL-10 could be detected in either TCRint population, implying a distinct function for these cells, different from those of conventional CD8+ and CD4+ cells, including the typical T-helper 2 (Th2) cell. Analysis of TCR expression indicated that the proportion of cells using the semi-invariant Valpha14/Vbeta8.2-type TCR was lower in NK1.1+ cells from MHC class II-negative mice than in CD4+NK1.1+ B6 cells. Further, usage of the Valpha14-J281 rearrangement was also demonstrated among NK1.1- TCRint cells.     

Oral immunization of interleukin-4 (IL-4) knockout mice with a recombinant Salmonella strain or cholera toxin reveals that CD4+ Th2 cells producing IL-6 and IL-10 are associated with mucosal immunoglobulin A responses.

Mucosal immunoglobulin A (IgA) responses are often associated with Th2-type cells and derived cytokines, and interleukin-4 (IL-4) knockout (IL-4-/-) mice with impaired Th2 cells respond poorly to oral antigens. However, we have noted that IL-4-/- mice have normal mucosal IgA levels, which led us to query whether different oral delivery systems could elicit mucosal immunity. Two oral regimens were used: (i) a live recombinant Salmonella strain which expresses fragment C (ToxC) of tetanus toxin, and (ii) soluble tetanus toxoid (TT) with cholera toxin (CT) as an adjuvant. Oral immunization of IL-4-/- mice with recombinant Salmonella vaccine expressing ToxC induced brisk mucosal IgA and serum IgG (mainly IgG2a) anti-TT antibody responses. TT-specific CD4+ T cells from spleen or Peyer's patches produced gamma interferon, indicative of Th1 responses; however, IL-6 and IL-10 were also seen. Oral immunization of IL-4-/- mice with TT and CT induced weak mucosal IgA to TT; however, brisk IgA anti-CT-B responses and CT-B-specific CD4+ T cells producing IL-6 and IL-10 were also noted. These results show that although IL-4-dependent antibody responses are impaired, mucosal IgA responses are induced in IL-4-/- mice. These result suggest that certain cytokines, i.e., IL-6 and IL-10 from Th2-type cells, play an important compensatory role in the induction and regulation of mucosal IgA responses.     

T-cell receptor antagonist modifies cytokine secretion profile of naive CD4+ T cells and their differentiation into type-1 and type-2 helper T cells

A T-cell receptor (TCR) antagonist is an analog of a peptide ligand for TCR that inhibits T-cell responses to the original peptide. We investigated the effects of a TCR antagonist on cytokine secretion of naive CD4+ T cells and their differentiation into type-1 and type-2 helper T cells (Th1 and Th2) induced by stimulation with varying doses of an antigenic peptide. In the presence of a TCR antagonist peptide, proliferation of naive CD4+ T cells and antigen dose-dependent secretion of interferon-gamma, a typical Th1-type cytokine, by these cells was down-regulated. With respect to the secretion of interleukin-4 (IL-4), a typical Th2-type cytokine, the TCR antagonist raised the concentration of the antigenic peptide required to elicit maximal IL-4 production and, surprisingly, significantly increased the maximum level of IL-4 secretion. Similar effects induced by the TCR antagonist were observed on the Th1/Th2 differentiation of naive CD4+ T cells. These results clearly indicate that, for naive CD4+ T cells, a TCR antagonist has the potential to change the balance of Th1/Th2 cytokine secretion and even enhance Th2 responses.     

Interleukin 12 and innate molecules for enhanced mucosal immunity

Recent strategies for understanding the mechanisms underlying mucosal immune responses and subsequent development of mucosal vaccines for induction of targeted immunity now include cytokines and molecules of innate immunity. These studies have shown that cytokines influencing the development of T helper (Th) cells differentially affect the outcome of mucosal vs. systemic immune responses to mucosal vaccines. Serum antigen-specific antibody (Ab) responses were enhanced when either IL-6 or IL-12 was mucosally administered with a protein antigen, while only IL-12 induced antigen-specific mucosal IgA Ab responses. Mucosal IL-6 and IL-12 also affected the type of Th cell responses induced by CD4+ T cells from mice that received IL-12 secreted larger amounts of IFN-gamma and IL-6 when compared with mice nasally treated with IL-6. Discrepancies in the ability to enhance mucosal or systemic immune responses were also observed when human neutrophil peptide (HNP) defensins or lymphotactin were nasally coadministered with protein antigens. Only lymphotactin promoted mucosal secretory IgA (S-IgA) Ab responses while both lymphotactin and defensins enhanced systemic immunity to mucosally co-administered protein antigens. Mixed antigen-specific Th1 -and Th2-type CD4+ T cell responses were induced in the systemic compartment by both lymphotactin and the mixture of HNP-1, HNP-2, and HNP-3 defensins. However, HNPs failed to significantly enhance cytokine secretion by mucosally derived, antigen-specific CD4+ T cells relative to those isolated from the systemic compartment. In summary, these studies clearly show that IL-12 and lymphotactin are able to trigger S-IgA Ab responses and provide new avenues for the design of safe and targeted mucosal vaccines.     

Regulatory functions for murine intraepithelial lymphocytes in mucosal responses

Our studies have given direct evidence that CD3+, CD4-, CD8+ T cells in the IELs can be separated into at least two subsets that produce IFN-gamma and/or IL-5 and may exhibit Th1- and Th2-type functions in the epithelium and in the underlying lamina propria region. Further, it was also shown that TCR1+ T cells in IELs are capable of producing IFN-gamma and/or IL-5. In addition to production of these cytokines, IELs derived from mice orally primed with TD antigen contain a subset of T cells which possess antigen-specific immunoregulatory function. CD3+, CD4-, CD8+ T cells isolated from IEL of TD antigen-primed mice abrogated systemic unresponsiveness to secondary-type responses including those of the IgA isotype upon adoptive transfer to mice with OT. Our studies further suggested that these CD3+, CD4-, CD8+ IELs use the gamma-delta form of TCR (TCR1) for their immunoregulatory function.     

Oral antigen induces antigen-specific activation of intraepithelial CD4+ lymphocytes but suppresses their activation in spleen

Intraepithelial lymphocytes (IELs) are considered to drive immune surveillance of the epithelial layer to the mucosa, which is initially exposed to exogenous antigens. However, how IELs are activated by orally administered antigens remains unclear. To clarify this mechanism, we fed ovalbumin (OVA) to T cell receptor transgenic (TCR-Tg) mice with OVA-specific MHC class II-restricted TCR and found that the cytotoxic activity of IELs was increased against both NK and LAK target cells, but notably reduced after depleting CD8 + IELs. Cytoplasmic staining showed that the production of IFN-gamma and IL-2 was increased in mice fed with OVA both in the supernatant of cultured IELs with immobilized anti-CD3 mAb and in fresh CD4+ IELs. In contrast, the cytotoxic activity against NK and LAK target cells and the production of IL-2 and IFN-gamma was decreased in splenic T cells from mice fed with OVA. However, when the splenic T cells from these mice were cultured with OVA and IL-2, IFN-gamma production recovered. The decreased response demonstrated the clonal anergy of T cells. Furthermore, tumor growth was enhanced in TCR-Tg mice carrying an OVA-transfected counterpart A20 B cell lymphoma (OVA-A20) and fed with OVA. These results indicate that the oral administration of soluble antigens can activate CD4+ IELs in an antigen-specific manner but induces hyporesponsiveness in the spleen. In addition, Th1-type cytokines produced by activated CD4+ IEL might provide a bystander effect on the cytotoxic activity of IELs.     

CD8-deficient mice exhibit augmented mucosal immune responses and intact adjuvant effects to cholera toxin.

We used normal, CD4 and CD8 gene-targeted mice to investigate the role of CD4+ and CD8+ T cells in the regulation of gut mucosal immune responses following oral immunizations with cholera toxin (CT) adjuvant. Phenotypic analysis of mucosa-associated tissues revealed normal CD3+ T-cell frequencies in CD4-/- and CD8-/- mice such that in CD4-/- mice the CD8+ and double-negative (DN) T cells were increased. In CD8-/- mice the CD4+ T cells were increased, with the exception that in the intraepithelial compartment the CD3+ T cells were predominantly DN gamma delta T-cell receptor (TCR)+ T cells. All mice, normal and deficient, failed to respond to oral immunization with the antigen, keyhole limpet haemocyanin (KLH), alone. In the presence of CT adjuvant, however, CD8-/- mice consistently exhibited three- to fivefold stronger gut mucosal responses compared to normal C57B1/6 mice. By contrast, no difference was observed for systemic responses between CD8-/- and normal mice. Thus the up-regulation selectively affected mucosal responses, suggesting that, contrary to the CD8-/- mouse gut, the normal gut mucosa may host CD8+ T cells that exert a local suppressive effect on T- and B-cell responses. The magnitude of the enhancing effect of CT was comparable in CD8-/- and normal mice, clearly demonstrating that the adjuvant mechanism of CT does not require CD8+ T cells. On the other hand, the adjuvant effect of CT required CD4+ T cells, because no or poor anti-KLH responses were observed in CD4-/- mice. In both normal and CD8-/- mice CT adjuvant promoted KLH-specific CD4+ T-cell printing without any selective effect on the differentiation towards a T-helper type-1 (Th1) or Th2 dominance. Furthermore, CT adjuvant increased the frequency of CD4+ T cells expressing a memory phenotype, i.e. CD44high, LECAM-1low and CD45RBlow. We have shown, using gene-targeted mice, that CD8+ T cells are not required for the adjuvant effect of CT, and that CD8+ T cells may exert local mucosal down-regulation of intestinal immune responses.     

Mucosal and systemic cellular immune responses induced by Toxoplasma gondii antigens in cyst orally infected mice.

This study was performed to determine the T-cellular immune responses following Toxoplasma gondii oral infection and to assess further toxoplasma antigens on their ability to stimulate in vitro mucosal and systemic T-cell immunity. Parasite-specific cellular immune responses in Peyer's patches (PP), in mesenteric lymph nodes (MLN) and in spleen (SPL) were investigated using a lymphoblastic transformation test following oral infection of mice with strain 76K cysts of T. gondii. An early toxoplasma sonicate-induced mucosal T-cell proliferation occurred in MLN and PP with a peak responsiveness on day 6 post-infection (PI) and rapidly reached background levels on day 7 PI in PP and on day 8 PI in mesenteric lymph nodes. A later splenic cellular blastogenesis was observed from day 28 PI and persisted throughout the experiment (day 91). At the time of T-cell proliferation, FACS analyses revealed a decrease in the relative percentages of CD4+ and CD8+ T cells with a predominance of CD8+ lymphocytes which leads to an inversion of the CD4/CD8 ratios. We found that CBA/J is a high responder mouse strain in the induction of mesenteric and splenic T-lymphocyte blastogenesis compared to the intermediate responder BALB/c and low responder C57BL/6. Toxoplasma gondii antigens SAG1 (30,000 MW) and GRA4 (40,000-41,000 MW), which are known to induce locally IgA antibodies, are shown to stimulate primed mucosal T lymphocytes from CBA/J and BALB/c mice whereas no proliferation was demonstrated with C57BL/6 T cells. 229-242 peptide, derived from the deduced amino acid sequence of GRA4, only induces detectable proliferation of primed-CBA/J T lymphocytes. Following oral experimental infection, the in vitro mesenteric response to a toxoplasma sonicate is dominated by a Th2-type cytokine pattern whereas a predominant Th1 cytokine response is observed in the spleen. Finally, in vitro stimulation of mesenteric T cells with the three defined toxoplasma antigens resulted in secretion of interleukin-5 (IL-5) and IL-6 (except for SAG1) and interferon-gamma (IFN-gamma) whereas no detectable IL-2 or IL-4 was observed.     

Dendritic cells in colonic patches and iliac lymph nodes are essential in mucosal IgA induction following intrarectal administration via CCR7 interaction

This study examined dendritic cells (DC) following intrarectal (IR) vaccination with the mucosal adjuvant cholera toxin (CT). Three rounds of IR vaccination with ovalbumin (OVA) and CT resulted in brisk levels of systemic and mucosal Ig responses. Immunohistochemical studies revealed that CD11c+ MHC class II+ cells accumulated primarily in the colonic patches (CP) and lamina propria of the large intestine (LI-LP), iliac LN (ILN) and MLN following IR vaccination with CT. Adoptively transferred CFSE-labeled OVA-specific CD4+ T cells proliferated significantly, secreting predominantly Th1-type cytokines in the CP (48 h after IR vaccination with CT) and Th2-type cytokines in the ILN (96 h after IR vaccination with CT). Following three IR vaccinations, CP-null mice that were generated by in utero treatment with anti-IL-7R Ab showed reduced levels of serum IgG and fecal IgA antibodies, suggesting a crucial role for CP in the initiation of systemic and mucosal immune responses. Of most interest, IR vaccination reduced IgA levels in fecal extracts significantly more in the CCR7-/- mice than in the wild-type mice. These results indicate that IR vaccination primarily mobilizes CD11c+ cells in the CP and ILN to induce optimal mucosal immune responses by CCR7 interaction.     

Expression of pro-inflammatory cytokines by TCRαβ+ T and TCRγδ+ T cells in an experimental model of colitis

An inflammatory bowel disease (IBD) comparable to human ulcerative colitis is induced upon transfer of T cell-depleted wild-type (F1) bone marrow into syngeneic T cell-deficient (tgε26) mice (F1 → tgε26). Previously we have shown that activated CD4⁺ T cells predominate in transplanted tgε26 mice, and adoptive transfer experiments verified the potential of these cells to cause disease in immunodeficient recipient mice. Using flow cytometry for the detection of intracellular cytokine expression, we demonstrate in the present study that large numbers of CD4⁺ and CD8⁺ TCRαβ⁺ T cells from the intraepithelial region and lamina propria of the colon of diseased, but not from disease-free mice, produced interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Large numbers of T cells from peripheral lymphoid tissues of these animals also expressed IFN-α and TNF-α, but few expressed interleukin-4, demonstrating g strong bias towards Th1-type T cell responses in these animals. TCRγδ⁺ T cells, typically minor constituents of the inflammatory infiltrate of the colon in F1 → tgε26 mice, also expressed IFN-γ at a high frequency upon CD3 stimulation. In light of these findings we examined the potential involvement of TCRγδ⁺ T cells by testing their ability to induce colitis in tgε26 mice. We report here that tgε26 mice transplanted with T cell-depleted bone marrow from TCRα^null and TCRβ^null animals developed IBD. Furthermore, disease in these mice correlated with the development of peripheral and colonic TCRαδ⁺ T cells capable of IFN-γ production. These results suggest that IFN-γ may be a common mediator of IBD utilized by pathogenic T cells of distinct phenotype.     

Characterization of fresh (uncultured) tumour-infiltrating lymphocytes (TIL) and TIL-derived T cell lines from patients with renal cell carcinoma.

Fresh (uncultured) TIL from 12 untreated patients with primary renal cell carcinoma were prepared from tumour specimens by enzymatic digestion, and were characterized by immunofluorescence using MoAbs recognizing leucocyte differentiation antigens or particular V alpha or V beta segments of the T cell receptor (TCR). These fresh TIL comprised CD3+ (20-84%); CD4+ (3-15%); CD8+ (13-35%); alpha beta TCR+ (20-50%); gamma delta TCR+ (3-17%); CD16+ (1-18%) and CD56+ (3-10%) cells. Significant proportions of V alpha 2+, V beta 5.1+ and V beta 6+ cells were found in TIL of certain patients with renal cell carcinoma, suggesting that they comprised oligoclonal T cells. T cell lines were developed in low concentrations of rIL-2 (200 U/ml) from TIL from 11 patients with renal cell carcinoma, and were characterized by immunofluorescence and cell-mediated cytotoxicity. These T cell lines consisted primarily of CD3+ (51-94%); CD4+ (1-80%); CD8+ (0-84%); alpha beta TCR+ (65-87%); gamma delta TCR+ (0-25%); CD16+ (0-16%) and CD56+ (2-57%) cells. These T cell lines exhibited non-specific cytotoxicity against autologous and allogeneic renal tumour cells, with the exception of one T cell line that exhibited preferential cytotoxicity against autologous renal tumour cells. These results suggest that fresh TIL from patients with renal cell carcinoma contain significant proportions of oligoclonal T cells that may have accumulated at the tumour site as a result of a clonal expansion.     

Splenic T helper cell type 1 cytokine profile and extramedullary haematopoiesis in severe combined immunodeficient (scid) mice with inflammatory bowel disease (IBD)

Scid mice develop a severe, chronic, and lethal IBD 3–6 months after engraftment of gut wall from immunocompetent congenic donors, induced by donor-derived CD4⁺ T cells migrating from the graft [ 7]. We have investigated intracellular T-helper type 1 (Th1) cytokines in the spleens of gut wall-transplanted scid mice with IBD. Increased fractions of interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and IL-2-positive CD4⁺ T cells were found in the spleens of diseased mice compared with control mice. Moreover, a small but significant population of CD4⁺ T cells which stained positive for granulocyte-macrophage colony-stimulating factor (GM-CSF) was found in scid mice with IBD but was virtually absent in congenic non-scid control mice. Cloning of granulocyte/macrophage colony-forming cells (G/M-CFC) revealed that both non-transplanted scid mice and scid mice with IBD had an 8–14-fold increase in splenic G/M-CFC compared with control mice. No significant difference in the number of G/M-CFC per total spleen was found between non-transplanted and disease scid mice, although both groups of mice showed a nearly two-fold increase compared with control mice. G/M-CFC were never found in the thymus, liver or lymph nodes of diseased mice. Immunohistochemistry revealed that the multinucleated giant cells observed in the gut wall of diseased mice did not represent haematopoietic foci, but were derived from macrophages. These observations point towards a dominant role for Th1-type CD4⁺ T cells in the immunopathogenesis of IBD, whereas haematopoiesis does not seem to be affected by the development of the disease.     

T helper cell dichotomy toCandida albicans: Implications for pathology,therapy, and vaccine design

Acquired immunity toCandida albicans is believed, to prevent mucosal colonization of adult immunocompetent individuals from progressing to symptomatic infection. Resistance to disease appears to correlate with the detection of delayed-type hypersensitivity responses in vivo and a T helper type 1 (Th1) cytokine secretion profile in vitro. Cellular immunodeficiency, particularly HIV infection, greatly increases the risk of mucosal infection, confirming that CD4+-cell-directed immunity is effective locally in controlling infectivity of the yeast. While Th1-type CD4+ cell activation resulting in phagocyte-dependent immunity clearly represents an important mechanism of anticandidal resistance, clinical observations suggest that Th2-type CD4+ cell reactivity may be triggered byCandida antigens in several disease states, including symptomatic infections and immunopathology. This may imply that a Th1-type pattern of reactivity characterizes the saprophytic yeast carriage and resistance to disease by healthy humans, whereas Th2-type responses would be mostly associated with pathology. More-over,Candida-specific T helper responses, namely humoral and cell-mediated immunity, appear to be reciprocally regulated, as typically occurs in experimental models of parasitic and retroviral infection, where the Th1/Th2 paradigm of acquired immunity has been best characterized. Recent studies, besides providing direct evidence for the occurrence of cross-regulatory Th1 and Th2 responses in mice with candidiasis, emphasize the potential of cytokine/anticytokine therapy for recruitingCandida-specific responses toward protective, Th1-type CD4+ cell reactivity. At the same time, these studies call attention to the possible consequences ofC. albicans infection for immunopathology, allergy, and coinfection.     

A novel surface molecule of Th2- and Tc2-type cells, CRTH2 expression on human peripheral and decidual CD4+ and CD8+ T cells during the early stage of pregnancy

It has been demonstrated that pregnancy induces the immunomodulation of cytokine responses away from the Th1 paradigm and towards the Th2 paradigm. In this study, we examined the expression of CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2) on decidual CD4+ and CD8+ T cells during the early stages of pregnancy. Examination of the cytokine profile revealed that CRTH2 was expressed on CD4+-type-2 T helper (Th2-type) and CD8+-type 2 T cytotoxic (Tc2-type) cells. The percentages of CRTH2+ cells in CD3+/CD4+ T cells and CD3+/CD8+ T cells were significantly higher in the decidua than in the peripheral blood. These results indicate the significance of Th2- and Tc2-type cells of the decidua in the maternal immune system, presumably through their production of cytokines which may contribute to the maintenance of pregnancy.     

T cells developing in fetal thymus of T-cell receptor alpha-chain transgenic mice colonize gammadelta T-cell-specific epithelial niches but lack long-term reconstituting potential

The gammadelta T cells generated during mouse fetal development are absolutely dependent on their invariant T-cell receptors (TCRs) for their function. However, there is little information on whether the epithelial homing properties of fetal T cells might also be developmentally induced by factors unrelated to TCR specificity. We have previously described TCR alpha-chain transgenic (2B4 TCR-alpha TG) mice, in which the transgenic TCR alpha-chain is expressed early, already at embryonic day 14 (E14). These mice have a large population of 'gammadelta T-cell-like' CD4- CD8- (double-negative; DN) alphabeta T cells, some of which develop during E14-E18 contemporarily to intraepithelial lymphocytes (IELs) expressing invariant TCR-gammadelta. Using the 2B4 TCR-alpha TG mouse model we have been able to more precisely study the impact of a variant TCR expression on IEL development and homing. In this study we show that TCR-alpha TG and TCR-alpha TG crossed to TCR-delta-deficient mice (TCR-alpha TG x TCR-delta-/-) carry TG TCR-alpha+ dendritic epidermal T cells (DETCs) and TCR-alpha TG+ IELs in the small intestine. The TG+ DETCs develop and seed the epidermis with similar kinetics as Vgamma5+ DETCs of normal mice, in contrast to the TCR-alphabeta+ DETCs found in TCR-delta-/- mice. However, whereas the intestinal TCR-alpha TG+ IELs persist in old mice (> 20 months), the TCR-alpha TG+ DETCs do not. The data in this study indicate that the timing of TCR expression and thereby development during ontogeny regulates the specific homing potential for fetal T cells but not their subsequent functions and properties.