Idiotype-recognizing T helper cells that are not idiotype specific

In this study T helper cells that recognize idiotypes as carriers for a hapten-specific B cell response were analyzed under limiting dilution conditions. T helper cells, induced by phosphorylcholine-hemocyanin (PC-Hy) priming, recognize trinitrophenylated TEPC-15 and MOPC-167 (TNP-T15, TNP-167) equally well. Limiting dilution analysis indicates identical frequencies of helper cells for TNP-T15 and TNP-167. Double immunization protocols using TNP-T15 and TNP-167 fail to demonstrate additive effects. Inhibition of carrier recognition in vitro using free hapten, PC, and unconjugated T15 or M167 indicates identical specificities of helper cells for T15 and M167. Collectively, these results provide strong evidence that PC-Hy priming induces only one population of idiotype-recognizing helper cells that are unable to distinguish between the T15 and the M167 idiotopes. The helper cell induction circuit was further analyzed. PC-Hy priming induces T15/167-specific helper T cells in X-linked immune defect-expressing F1 mice. This indicates that a B cell response to PC is not required to induce idiotype-recognizing T cells. Adoptive cotransfer of B cells from PC-Hy-primed mice together with normal T cells fails to induce idiotype-recognizing T cells. These results indicate the existence of a T helper1-T helper2 induction loop. In this scheme, the T helper1 cell carries T15-like receptors and the T helper2 cells, anti-T15-like receptors. Monoclonal antiidiotypic antibodies specific for T15 also induce a T15/167-recognizing T helper cell population. This finding demonstrates that idiotope-specific priming induces non-idiotype-specific T cells. Evidently, the idiotypic T cell network is based on a different selection of idiotope determinants than the selection of the B cell idiotype network.     

Helper T cells for cytotoxic T lymphocytes need not be I region restricted

We investigated the antigenic requirements for restimulation of H-2- restricted cytolytic T lymphocytes (CTL) in vitro to determine whether H-2 I region-restricted helper T cells are required in these responses. In one set of experiments, we studied the in vitro response of (responder x nonresponder)F(1) female T cells to the male antigen H-Y. We chose to examine this response because it has been suggested that the defect in nonresponder strains is a failure of helper T cells to recognize H-Y in association with nonresponder I region determinants. However, we find that nonresponder male stimulator cells are as effective as F(1) male stimulator cells at inducing H-Y-specific CTL responses. This finding calls into question reports that secondary CTL responses to H-Y are dependent upon the activation of H-Y- specific helper T cells restricted to responder type I region determinants. In a second set of experiments, we examined the requirements for restimulation of H-2-restricted T cells specific for minor-histocompatibility antigens from long-term mixed lymphocyte cultures. These cultures were established by repeatedly restimulating cultures of specific T cells with H- 2-matched stimulator cells expressing foreign minor histocompatibility antigens. We found that H-2D-restricted T ceils, including CTL, could be restimulated with cells that were matched with the responding cells at only the D region genes. This response did not appear to result from positive allogeneic effects or from antigen processing and “representation” by responder type APC that might contaminate the cultures. Thus, we find no evidence for a requirement for I region-restricted helper T cells in these CTL responses. However, helper T cells are required because we find that CTL lines derived by limit-dilution cloning from these long-term MLC are absolutely dependent upon exogenous helper factors for growth. The most simple interpretation of these results is that the helper cells are restricted to H-2 antigens other than I region antigens or to antigens that code outside of the H-2 complex. Finally, we show that factor-dependent CTL lines must recognize their specific antigen to proliferate, even in the presence of exogenous factors. The requirement of activated CTL for antigen to proliferate provides an explanation for how specific CTL can be selectively enriched in MLC by specific antigen stimulation. Furthermore, it is at variance with reports that memory CTL or activated CTL require only interleukin 2 for restimulation.     

Survivin-specific T cell receptor targets tumor but not T cells

Survivin is a tumor-associated antigen (TAA) that inhibits apoptosis and is widely overexpressed in cancer cells; therefore, survivin has potential as a target for cancer immunotherapy. Application of HLA-A2–restricted survivin-specific T cell receptors (TCRs) isolated from allogeneic HLA–mismatched TCR repertoires has, however, been impeded by the inability of these TCRs to distinguish healthy cells expressing low levels of survivin from cancer cells with high survivin expression levels. Here, we identified an HLA-A2–restricted survivin-specific TCR isolated from autologous TCR repertoires that targets tumor cells in vitro and in vivo but does not cause fratricidal toxicity. Molecular modeling of the TCR-peptide-HLA ternary complexes and alanine scanning revealed that the autologously derived TCRs had tighter interactions with the survivin peptide than did fratricidal TCRs. Similar recognition patterns were observed among 7 additional TAA-specific TCRs isolated from allogeneic versus autologous repertoires. Together, the results from this study indicate that maximal peptide recognition is key for TCR selectivity and likely critical for reducing unwanted off-target toxicities. Moreover, isolating TCRs from autologous repertoires to maximize TCR selectivity has potential as a useful strategy to identify and select other shared tumor- and self-antigen–specific TCRs and ensure selective antitumor activity.     

Antigen-specific helper T cells required for dominant idiotype expression are not H-2 restricted

Two synergizing antigen-specific helper T (Th) cell populations are required for an optimal TEPC15 (T15)-dominated antiphosphorylcholine (PC) plaque- forming cell response . In these studies, the two Th cell sets are shown to differ in their requirements for recognition of self-major histocompatibility complex (MHC)-encoded determinants by testing the ability of Th cells from F(1) {arrow} parent bone marrow chimeras to collaborate with PC-specific B cells bearing MHC-encoded determinants of either parental haplotypes. Previous studies have shown that one antigen-specific Th cell population is required for T-dependent anti-PC responses and activates PC-specific B cells only if the hapten, PC, is physically linked to the priming antigen. This Th cell, referred to as ThMHC, induces anti-PC responses that are mainly non-T15 in character, and it appears to be identical to the conventional antigen- specific Th cell. In these experiments, using T cells from (A X B)F(1) {arrow} parent A chimeras, ThMHC cells requiring hapten-carrier association provide help for F(1) and parent A B cells but not for B cells from parent B, thus confirming that the activity of the conventional Th cell is H-2 restricted . The second antigen-specific Th cell population, whose function is measured in the presence of the ThMHC cell set, preferentially activates T15-bearing B cells. This Th cell set (ThId) is missing in mice expressing low levels of T15-bearing antibody and can be restored by the addition of antigen-specific T cells from donors expressing high levels of circulating T15 Id. These studies demonstrate that T cells from F(1) {arrow} parent chimeras that express substantial levels of T15-bearing anti-PC antibody could provide ThId cell activity for the selective activation of T15-bearing B cells of F(1) and both parental H-2 types. These results imply that whereas the activity of conventional, ThMHC, cells is clearly H-2 restricted, ThId cells from the same chimeric donors are not required to recognize antigen in association with self-MHC-encoded determinants for successful T-B collaboration .     

Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells.

Thymic epithelial cell lines (TECs) were established from newborn C57BL/6 mice. They were classified into two types (medullary and cortical TECs) by using the monoclonal antibody (Th-3) that recognizes the meshwork structure of thymic cortical epithelial cells. Antigen-presenting activity of each TEC was determined by using ovalbumin-specific, I-Ab-restricted helper T cell lines. It was demonstrated that the medullary but not the cortical TECs functioned as antigen-presenting cells. This is the first evidence for the functional difference between the cortical and the medullary TEC.     

P-Selectin Glycoprotein Ligand-1 (PSGL-1) on T Helper 1 but Not on T Helper 2 Cells Binds to P-Selectin and Supports Migration into Inflamed Skin

We have shown recently that mouse Th1 cells but not Th2 cells are selectively recruited into inflamed sites of a delayed-type hypersensitivity (DTH) reaction of the skin. This migration was blocked by monoclonal antibodies (mAb) against P- and E-selectin. Here we show that Th1 cells bind to P-selectin via the P-selectin glycoprotein ligand-1 (PSGL-1). This is the only glycoprotein ligand that was detectable by affinity isolation with a P-selectin–Ig fusion protein. Binding of Th1 cells to P-selectin, as analyzed by flow cytometry and in cell adhesion assays, was completely blocked by antibodies against PSGL-1. The same antibodies blocked partially the migration of Th1 cells into cutaneous DTH reactions. This blocking activity, in combination with that of a mAb against E-selectin, was additive. PSGL-1 on Th2 cells, although expressed at similar levels as on Th1 cells, did not support binding to P-selectin. Thus, the P-selectin–binding form of PSGL-1 distinguishes Th1 cells from Th2 cells. Furthermore, PSGL-1 is relevant for the entry of Th1 cells into inflamed areas of the skin. This is the first demonstration for the importance of PSGL-1 for mouse leukocyte recruitment in vivo.     

Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.     

Helper and killer T cells do not express B cell immunoglobulin joining and constant region gene segments

We have analyzed four kinds of T cells for rearrangement and expression of immunoglobulin genes. These cells include: (a) whole thymus; (b) WEHI-22, a T-cell lymphoma; (c) HT-1, an major histocompatibility complex-restricted T helper line; and (d) CTLLi6, an H-2 alloreactive killer cell line. None of the B-cell joining and constant gene segments are rearranged in the T cells. The monoclonal cells do not express any C kappa, C lambda, Cmu or C alpha RNA species. Small amounts of C kappa, C alpha, and Cmu sequences are present in RNA prepared from the thymus, although the significance of this RNA for T-cell antigen receptor synthesis is uncertain. The data support the hypothesis that expression of B-cell joining and C gene segments is unnecessary for T- cell helper and T-cell killer activity.     

Cellular and genetic control of antibody responses. V. Helper T-cell recognition of H-2 determinants on accessory cells but not B cells

Requirements for helper T-cell recognition of H-2 determinants expressed on adherent accessory cells and on B cells was individually assessed in the anti-hapten PFC responses to TNP-KLH. Complicating allogeneic effects were minimized or avoided by the use of helper T cells from normal F1 hybrids, parent leads to F1 chimeras, and F1 leads to parent chimeras. The results of both in vitro and in vivo experiments demonstrated that: (a) helper T cells are not required to recognize the identical H-2 determinants on both accessory cells and B cells; (b) helper T cells are required to recognize K or I-A region-encoded determinants expressed on accessory cells; (c) no requirement was observed in vitro or in vivo for helper T-cell recognition of B-cell-expressed H-2 determinants; and (d) no requirement was observed for H-2 homology between accessory cells and B cells. The absence of required helper T-cell recognition of the identical H-2 determinants on both accessory cells and B cells was demonstrated in two ways: (a) naive of KLH-primed (A x B)F1 hybrid helper T cells collaborated equally well with B cells from either parentA or parentB in the presence of accessory cells from either parent; (b) A leads to (A x B)F1 chimeric spleen cells depleted of accessory cells collaborated equally well with accessory cells from either parentA or parentB, even though the B cells only expressed the H-2 determinants of parentA. A requirement for helper T-cell recognition of K or I-A region-encoded H-2 determinants on accessory cells was also demonstrated in two ways: (a) (A x B)F1 leads to parentA chimeric spleen cells depleted of accessory cells collaborated with accessory cells from parentA but not parentB; and (b) (A x B)F1 leads to parentA chimeric helper T cells collaborated with normal F1 B cells only in the presence of parental or recombinant accessory cells that expressed the K or I-A region-encoded determinants of parentA. Although restricted in their ability to recognize H-2 determinants on accessory cells, it was demonstrated both in vitro and in vivo that (A x B)F1 leads to parentA chimeric helper T cells were able to collaborate with B cells from either parentA or parentB. In vitro in the presence of accessory cells from parentA, (A x B)F1 leads to parentA chimeric helper T cells collaborated equally well with B cells from either parent. In addition, the inability of (A x B)F1 leads to parentA chimeric helper T cells to collaborate with (B + accessory) cells from parentB was successfully reversed by the addition of parentA SAC as added accessory cells. In vivo, upon the addition of parentA accessory cells, (A x B)F1 leads to parentA chimeric helper T cells collaborated with parentB B cells in short-term adoptive transfer experiments.     

Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma–delta T cells

Background Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T‐ and B‐lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma/delta T cells has still not been evaluated. Gamma–delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft‐vs.‐host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes. Materials and methods Peripheral blood mononuclear cells from 21 healthy donors were used as source for gamma–delta T cells, expanded in presence of 10 IU mL^?1 interleukin‐2 (IL‐2) and 1 μM zoledronate. MSCs were recovered from patients undergoing routine total hip replacement surgery, and characterised by flow cytometry. Cytotoxicity on multiple myeloma and melanoma cell lines was assessed by measuring dilution of the carboxyfluorescein diacetate succinimydylester dye (CFSE). Gamma–delta T cells were then incubated with MSCs in contact cultures, and with addition of MSC‐conditioned medium. Results In this article we confirmed that (1) in vitro expanded gamma–delta T cells play a significant anti‐proliferative effect on multiple myeloma and melanoma cells and (2) multipotent mesenchymal stromal cells effectively suppress the ex vivo expansion of T cells carrying a specific T‐cell receptor gene (TCR) rearrangement, Vgamma9/Vdelta2, induced by the combination of IL‐2 and zoledronate, without interfering with their cytotoxic activity. Discussion These findings contribute to explain the activity of ex vivo expanded mesenchymal cells, suggesting that MSCs would interact with gamma–delta T lymphocytes. Conclusion This effect could be relevant in separating graft‐vs.‐host from the graft‐vs.‐tumour effect, especially considering the possibility of modulating T‐lymphocytes activity by the immunomodulating drugs now available.     

Neuropilin 1 is expressed on thymus-derived natural regulatory T cells,but not mucosa-generated induced Foxp3+ T reg cells

Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-β. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1^low. We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.The powerful effects of Foxp3⁺ regulatory T cells are illustrated by the devastating inflammatory diseases caused by Foxp3 mutations in mice and humans (Bennett et al., 2001; Brunkow et al., 2001; Wildin et al., 2001). As a consequence, experimental or clinical manipulation of the entire Foxp3⁺ T reg compartment could have catastrophic consequences (Kim et al., 2007).It has been proposed that, because of their different developmental origin and TCR repertoires, Foxp3⁺ nT reg and iT reg cells could have some nonoverlapping regulatory functions in vivo (Bluestone and Abbas, 2003; Curotto de Lafaille and Lafaille, 2009; Haribhai et al., 2009). It was recently shown that to completely prevent mortality and inflammation in Foxp3-deficient mice, both nT reg and iT reg cells were necessary (Bilate and Lafaille, 2011; Haribhai et al., 2011).The nonoverlapping functions of nT reg and iT reg cells raise the possibility of selective intervention strategies that would not affect all T reg cells—only nT reg or iT reg cells, or subsets of them. A major barrier to such an approach is the lack of suitable surface markers that distinguish nT reg and iT reg cell populations. The aforementioned studies addressing the issue of division of labor required very specialized strains of mice. However, these experimental systems cannot be used to identify nT reg and iT reg cells in unmanipulated WT mice. In this study, we show that surface expression of Neuropilin 1 (Nrp1) is preferentially up-regulated by nT reg cells in WT mice, and that, in contrast, iT reg cells generated under several in vivo conditions, including the physiologically relevant mucosal route, express low levels of surface Nrp1.     

Helper T cells are required for the polyclonal stimulation of cytotoxic T cells by concanavalin A

Concanavalin A stimulation of T-cell cytotoxicity has been shown to be absolutely dependent on helper T-cell collaboration. Thymocytes stimulated with ConA do not differentiate to yield cytotoxic effector cells. However, thymocytes cocultured with irradiated spleen cells as helpers and ConA yield high levels of cytotoxicity. The helper cell bears theta antigens on its surface, is not an adherent cell, and does not require any adherent cell functions in our culture conditions. The ConA-dependent helper cells appear to be polyclonal in specificity. Thus, polyclonal stimulation of cytotoxicity by ConA requires T helper-T precursor collaboration in analogy to antigen-specific T helper-T precursor interactions. Unlike the antigen-specific interacitons, the ConA-driven cytotoxicity does not appear to require linked associative recognition for induction of cytotoxicity.     

Suppression of idiotype and generation of suppressor T cells with idiotype-conjugated thymocytes

Inoculation of A/J mice with syngeneic thymocytes conjugated with specifically purified A/J anti-phenylarsonate (anti-Ar) antibodies, selectively suppressed the subsequent synthesis of those anti-Ar antibodies which carry the major cross-reactive idiotype. High titers of anti-Ar antibodies were produced upon subsequent immunization but in most mice the idiotype was undetectable. Suppression similarly occurred in F1(A/J X BALB/c) and in C.AL-20 mice. Although some mice were suppressed when unconjugated antibody was injected, the suppressive effect was much more pronounced, particularly in the F1 and C.AL-20 recipients, when the antibody was coupled to thymocytes. The state of suppression could be adoptively transferred with T cells to mildly irradiated syngeneic recipients. A population enriched for B cells had little if any suppressive effect. There was no requirement for antigen in the generation of suppressors. Thymocytes conjugated with antibody did not induce idiotype-specific suppression in mice that had been recently challenged with antigen. Thymocytes from BALB/c and C57BL/10 mice were effective carriers for the anti-Ar antibodies, i.e., there was no evidence for H-2 restriction. The experiments demonstrate the feasibility of suppressing idiotype production and generating idiotype-specific suppressor T cells without the use of anti-idiotypic antibody or antigen.     

滤泡辅助T细胞的研究进展

B细胞产生抗体需要T细胞辅助。最近研究发现一种命名为滤泡辅助T细胞（TFH）的T细胞亚群,它们被认为是B细胞最主要的辅助细胞,是淋巴组织中最常见和最重要的效应T细胞亚群之一。TFH与Th1和Th2存在明显差别,其趋化因子受体表达为CXCR5,定位和迁移于B细胞滤泡,具有辅助B细胞功能。TFH细胞分泌辅助细胞因子IL-21,通过与B细胞上IL-21R结合,使之分化为产生抗体的细胞。TFH细胞功能调节异常或TFH细胞相关分子表达异常,可能与某些自身免疫性疾病、免疫缺陷病和恶性肿瘤的发病机制有关。本文就CXCR5和TFH细胞的发现、TFH细胞的起源与TFH细胞功能相关的细胞因子,TFH效应细胞和记忆细胞的迁移和定位、TFH细胞异常与疾病等问题进行了综述。     

NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses

The canonical NF-κB pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-κB pathway and its central mediator NF-κB-inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of T(H)17 cells, and its absence in T(H) cells renders them incapable of inducing autoimmune responses, suggesting a T cell-intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4(+) T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4(+) T cells and that DC-restricted expression of NIK is sufficient to restore T(H)1 and T(H)17 responses as well as cell-mediated immunity in NIK(-/-) mice. When CD4(+) T cells developed in the absence of NIK-sufficient DCs, they were rendered anergic. Reintroduction of NIK into DCs allowed developing NIK(-/-) CD4(+) T cells to become functional effector populations and restored the development of autoimmune disease. Therefore, our data suggest that a population of thymic DCs requires NIK to shape the formation of most αβ CD4(+) T effector lineages during early development.     

Presence on idiotype-specific suppressor T cells of receptors that interact with molecules bearing the idiotype

All A/J mice produce anti-p-azophenylarsonate (anti-Ar) antibodies, some of which share a cross-reactive idiotype. The idiotype can be suppressed by treatment with anti-idiotypic antiserum before immunization, although normal concentrations of anti-Ar antibodies are synthesized. We have previously reported that such suppressed mice, if hyperimmunized and then allowed to rest, contain up to 10% of splenic T cells which form rosettes with autologous RBC coated with Fab fragments of anti-Ar antibodies bearing the idiotype. Our present results indicate that the rosette-forming T cells include the idiotype-specific suppressor T-cell population. The suppressive activity is largely depleted by removal of the rosette-forming lymphocytes, and the rosettes themselves are highly suppressive. The data do not establish whether all of the idiotype-specific rosette-forming cells are suppressor cells. The system may provide a source of large numbers of suppressor cells for further study, and facilitate investigation of the mechanism of generation of idiotype-specific suppressor cells.     

T cell aging: naive but not young

The immune system exhibits profound age-related changes, collectively termed immunosenescence. The most visible of these is the decline in protective immunity, which results from a complex interaction of primary immune defects and compensatory homeostatic mechanisms. The sum of these changes is a dysregulation of many processes that normally ensure optimal immune function. Recent advances suggest that old mice can produce fully functional new T cells, opening both intriguing inquiry avenues and raising critical questions to be pursued.     

Selective Expression of a Stable Cell Surface Molecule on Type 2 but Not Type 1 Helper T Cells

T helper cell type 1 (Th1) and 2 (Th2) are central to immune regulation. However, no stable cell surface marker capable of distinguishing and separating these two subsets of CD4⁺ cells has yet been found. Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli. Antibody against a peptide derived from ST2L strongly and stably labeled the surface of cloned Th2s but not Th1s, and Th2s but not Th1s derived from naive T cells of ovalbumin T cell receptor–α/β transgenic mice. Three-color single cell flow cytometric analysis shows that cell surface ST2L coexpressed with intracellular interleukin (IL)-4, but not with interferon (IFN)-γ. The antibody selectively lysed Th2s in vitro in a complement-dependent manner. In vivo, it enhanced Th1 responses by increasing IFN-γ production and decreasing IL-4 and IL-5 synthesis. It induced resistance to Leishmania major infection in BALB/c mice and exacerbated collagen-induced arthritis in DBA/1 mice. Thus, ST2L is a stable marker distinguishing Th2s from Th1s and is also associated with Th2 functions. Hence, it may be a target for therapeutic intervention.