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The Journal of Immunology, 2002, 169: 4124-4128.
Copyright © 2002 by The American Association of Immunologists

Neonatal Tolerance in the Absence of Stat4- and Stat6- Dependent Th Cell Differentiation1

Hua-Chen Chang, Shangming Zhang and Mark H. Kaplan2

Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202; and Walther Cancer Institute, Indianapolis, IN 46208


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neonatal tolerance to specific Ag is achieved by nonimmunogenic exposure within the first day of life. The mechanism that regulates this tolerance may provide the basis for successful organ transplantation and has recently been thought to be immune deviation from the inflammatory Th1 response to a Th2 response. To test the importance of Th2 cells in the establishment of neonatal tolerance, we examined neonatal tolerance in Stat4- and Stat6-deficient mice, which have reduced Th1 and Th2 cell development, respectively. Neonatal tolerance of both the T and B cell compartments in Stat4- and Stat6-deficient mice was similar to that observed in wild-type mice. Cytokine production shifted from a Th1 to a Th2 response in wild-type mice tolerized as neonates. In contrast, tolerance was observed in Stat6-deficient mice despite maintenance of a Th1 cytokine profile. These results suggest that cells distinct from Stat6-dependent Th2 cells are required for the establishment of neonatal tolerance.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Five decades ago, Medawar and colleagues (1) established that fetal and neonatal mice could be tolerized to alloantigen, such that the mice could later accept allografts. Both B and T cells become nonresponsive to specific Ag in the tolerant state (2, 3). Despite a considerable amount of examination, the mechanism of neonatal tolerance is still unclear. Possibilities include clonal inactivation, suppression, clonal deletion, and immune deviation (4, 5, 6, 7, 8). Indeed, several mechanisms may play a role in specific experimental systems of tolerance induction.

Immune deviation has received considerable attention since the initial description that Ag-stimulated neonatal T cells secrete IL-4, a hallmark Th2 cytokine (9). Subsequent studies have demonstrated that administration of IL-12, IFN-{gamma}, or anti-IL-4 with the tolerogen eliminates tolerance, supporting a Th1/Th2 paradigm (10, 11, 12, 13). Neonatal exposure to various immunogens, including alloantigen, viral Ags, and protein Ags, results in an Ag-specific Th2 response (4, 5, 7, 14). However, whether the Th2 response is causative of the tolerant state or is a simple by-product of the dampening of the Th1 response has not been determined.

The development of Th1 cells is promoted by IL-12 and the activation of Stat4 (15, 16, 17). Stat4-deficient mice lack many IL-12-stimulated responses, including the induction of IFN-{gamma} secretion and the differentiation of Th1 cells (18, 19). Because of this phenotype, Stat4-deficient mice are susceptible to infection with Trypanosoma cruzi, Toxoplasma gondii, and Leishmania major and have decreased delayed-type hypersensitivity responses (20, 21, 22, 23). In contrast, Stat4-deficient mice are refractory to the induction of colitis and experimental autoimmune encephalomyelitis (24, 25). T cell memory responses in Stat4-deficient mice generate little IFN-{gamma} (20, 22, 24, 25, 26). Ab responses to Schistosoma mansoni and L. major at later time points indicate a marked decrease in IgG2a and IgG3 production, while there is no significant difference in Ab development to T. cruzi or myelin oligodendrocyte glycoprotein (20, 21, 22, 25). While in vitro assays suggest that Stat4 deficiency results in greater Th2 differentiation, this is only true in some in vivo models (20, 22, 25, 27). Thus, the phenotype of the Stat4-deficient model is that of a mouse with greatly impaired Th1 responses in vivo.

Th2 cell development is stimulated by IL-4-activated Stat6 (28, 29, 30). Stat6-deficient mice lack IL-4- and IL-13-stimulated responses and have impaired Th2 cell differentiation (31, 32, 33). Stat6 has been shown to be required in both T and non-T cells for normal immune responses to the parasites Nippostrongylus brasiliensis, S. mansoni, Trichinella spiralis, and Taenia crassiceps (20, 33, 34, 35, 36). However, some T cell production of IL-4 can be observed in Stat6-deficient mice infected with N. brasiliensis, T. spiralis, Heligmosomoides polygyrus, and S. mansoni and by stimulation of NK T cells, presumably through Stat6-independent expression of GATA3 (37, 38, 39, 40). Stat6 is also required for contact hypersensitivity and regulation of some models of autoimmunity (41, 42). Because Stat6-deficient mice have decreased Th2 generation in vivo, they also have increased Th1 activity that results in enhanced immunity to L. major, Leishmania mexicana, ectromelia, and T. cruzi and enhanced susceptibility to experimental autoimmune encephalomyelitis (21, 22, 25, 43, 44). Importantly, Stat6 is required for susceptibility to allergic asthma (45, 46, 47, 48). Stat6 is required for IL-4-induced class switching to IgE and IgG1, and Stat6-deficient mice demonstrate enhanced IgG2a class switching in vivo (20, 21, 31, 32, 33, 45, 46, 47, 49). Thus, Stat6-deficient mice display a dramatic inhibition of the ability to generate Th2 cells and have enhanced Th1-mediated immunity in vivo.

In this report we have used Stat4- and Stat6-deficient mice to determine the role of Th subsets in neonatal tolerance. We found that T and B cell tolerance is similarly established in wild-type, Stat4-deficient, and Stat6-deficient mice. While cytokine deviation is observed in wild-type mice, a Th1 cytokine profile is concomitant with tolerance in Stat6-deficient mice. Thus, Stat6-dependent Th2 cells are not required for neonatal tolerance.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

Generation of Stat4- and Stat6-deficient mice has been described (18, 31), and mice were backcrossed 10 generations to the BALB/c genetic background. Control (wild-type BALB/c) mice were purchased from Harlan Bioproducts (Indianapolis, IN). Experiments were performed following approval from the Indiana University animal care and use committee.

Tolerization or immunization

Neonatal mice were injected i.p. with 100 µg hen egg lysozyme (HEL3; Sigma-Aldrich, St. Louis, MO) or PBS alone emulsified in IFA (Calbiochem, San Diego, CA) in a total volume of 0.1 ml using a 1-ml syringe and a 26-gauge needle. At 6 wk of age mice were immunized s.c. with 50 µg HEL in CFA (Calbiochem) in a total volume of 0.1 ml. Fourteen days after immunization, mice were sacrificed, and spleen cells, draining lymph node cells, and serum were collected from each mouse.

Proliferation assays

Lymph node and spleen cells (5 x 104/well) were stimulated in the absence or the presence of increasing doses of HEL (range, 62–500 µg/ml). After 72 h in culture, microtiter plates were pulsed with 0.8 µCi [3H]thymidine. Plates were harvested after 18 h and were counted in a scintillation counter. Cultures were stimulated with 2.5 µg/ml Con A as a control.

ELISA

For detection of Ag-specific Ab titers, ELISA plates were coated with 5 µg/ml HEL. Sera were diluted 1/10 in PBS and 2% BSA and were tested at serial 2-fold dilutions using isotype-specific Abs for detection (BD PharMingen, San Diego CA). Titers (arbitrary units) were calculated by multiplying the half-maximal OD by the dilution (20). Cytokines levels were tested using specific Abs purchased from BD PharMingen (IL-5 and IFN-{gamma}).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Neonatal tolerance is associated with immune deviation from a Th1 to a Th2 response. We hypothesized that the decreased ability of Stat4-deficient and Stat6-deficient mice to generate Th1 and Th2 cells, respectively, would discern the requirement for these cells during the establishment of tolerance. To tolerize neonates, wild-type, Stat4-deficient, and Stat6-deficient BALB/c mice were injected i.p. with HEL emulsified in IFA or with PBS/IFA as a control within the first day of life. At 6 wk of age mice were challenged with HEL emulsified in CFA. Proliferative responses were tested 14 days later. Draining lymph node or spleen cells were stimulated with increasing concentrations of HEL or were incubated in the absence of HEL. Fig. 1Go represents the collection of data from six independent experiments, and stimulation indexes were calculated at one concentration (250 µg/ml) of HEL. Fig. 1GoA demonstrates that neonatal tolerance is established in all three genotypes. Mice that did not receive HEL as neonates had greater responses than neonatally tolerized mice. The reduction in stimulation index was statistically significant for all groups (p < 0.03). As has been seen in several other systems (5, 50), tolerance was only established in lymph nodes, and spleen cells remained equally responsive to HEL stimulation regardless of neonatal tolerance or genotype of the mice (Fig. 1GoB). To further demonstrate the level of tolerance, we determined the percentage of mice in each group that had a stimulation index >3 (high responders). Fig. 1GoC demonstrates that there was little difference in the percentage of high responders in spleen cells from all groups of mice or in the percentage of high responders from nontolerized lymph node cells. However, in lymph node cells there was a dramatic decrease in the percentage of high responders in the tolerized groups compared with nontolerized groups of all three genotypes of mice. As a control for the ability of T cells to proliferate, we stimulated lymph node cells from all three genotypes with Con A. Wild-type, Stat4-deficient, and Stat6-deficient lymph node cells had similar levels of Con A-induced proliferation regardless of the induction of tolerance (data not shown). Thus, T cells maintain the ability to proliferate in response to a polyclonal stimulus.



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  		FIGURE 1. Establishment of neonatal T cell tolerance in wild-type, Stat4-deficient, and Stat6-deficient mice. Neonatal mice (<12 h old) were i.p. injected with IFA or HEL emulsified in IFA (tolerized). At 6 wk of age both groups of mice were immunized with HEL emulsified in CFA s.c. After 14 days mice were sacrificed, and proliferative responses to 250 µg/ml HEL were assessed by [3H]thymidine incorporation. Stimulation indexes were calculated for each mouse. The results shown are pooled from several experiments. {circ}, Fold stimulation of one mouse. Bars represent the average ± SEM of each group. Statistical significance was determined using Student’s t test. Results are shown for proliferation in the draining lymph nodes (A) and spleen (B). C, The percentage of high responders (stimulation index, >3) was determined for each of the groups in A and B.

 
To determine the level of B cell tolerance we assayed the level of Ag-specific Abs in the serum of mice treated as described above. Wild-type mice not given HEL as neonates generated both IgG1 and IgG2a Ag-specific Abs following immunization (Fig. 2Go). However, the HEL-tolerized group generated low titers of HEL-specific Abs of both isotypes. Stat4-deficient mice mounted a predominantly IgG1 response to HEL following immunization, with little Ag-specific IgG2a produced, correlating with low IFN-{gamma} levels in vivo and as seen previously. By contrast, Stat6-deficient mice had almost exclusively IgG2a anti-HEL titers. This correlates with decreased class switching to IgG1 in Stat6-deficient B cells (49). Importantly, both Stat4- and Stat6-deficient mice were unable to generate significant titers of anti-HEL when they were neonatally tolerized, similar to wild-type mice.



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  		FIGURE 2. Establishment of neonatal B cell tolerance in wild-type, Stat4-deficient, and Stat6-deficient mice. Mice of the indicated genotype were tolerized and/or immunized as described in Fig. 1Go. At sacrifice, serum from each mouse was obtained and tested for levels of Ag-specific isotypes by ELISA. Titers (arbitrary units) were calculated by multiplying the half-maximal OD by the dilution. Results shown are pooled from several experiments. {circ}, Titer of one mouse. Bars represent the average ± SEM of each group. Statistical significance was determined using Student’s t test. Results are shown for IgG1 (A) and IgG2a (B)-specific Abs. One IgG1 arbitrary unit is approximately equivalent to 25 ng/ml. One IgG2a arbitrary unit is approximately equivalent to 45 ng/ml.

 
To determine the level of immune deviation of these mice, we examined supernatants of Ag-stimulated lymph node cells from mice treated as described above. IL-4 levels were low or undetectable in many samples; thus, IL-5 was used as a marker for Th2 responses, and IFN-{gamma} was used as a marker for Th1 cells. Wild-type mice that did not receive HEL as neonates had high IFN-{gamma} and low IL-5 following immunizations and thus a high IFN-{gamma}/IL-5 ratio, indicating the Th1/Th2 ratio (Fig. 3Go). The induction of tolerance in wild-type mice resulted in a significant increase in IL-5 secretion, although with no significant change in IFN-{gamma} levels, indicating a decrease in the Th1/Th2 ratio (p = 0.01). In contrast, Stat4-deficient mice had a low ratio, indicating higher Th2 activity than Th1, although there were relatively low levels of both IFN-{gamma} and IL-5 production (Fig. 3Go). Tolerance had no significant effect on the cytokine production in Stat4-deficient cultures (p > 0.05). Stat6-deficient mice had high IFN-{gamma} and low IL-5 production, indicating low Th2 activity. The establishment of tolerance in Stat6-deficient mice did not alter this pattern of cytokine secretion (p > 0.05). Thus, tolerance induction was not accompanied by significant immune deviation in either the Stat4- or Stat6-deficient mice. Therefore, neonatal tolerance does not require Stat4- or Stat6-dependent immune deviation.



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  		FIGURE 3. Immune deviation following tolerance in wild-type, Stat4-deficient, and Stat6-deficient mice. Mice of the indicated genotype were tolerized and/or immunized as described in Fig. 1Go. At sacrifice, lymph node cells were stimulated with Ag (500 µg/ml), and supernatants were recovered after 72 h for analysis of cytokine levels by ELISA. IFN-{gamma} and IL-5 production is shown as the average of least six mice individually determined and pooled from two separate experiments. Ratios of IFN-{gamma} to IL-5 are calculated from individual mice. A high ratio indicates Th1 skewing, while a low ratio indicates a Th2 environment.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the 5 decades that the phenomenon of neonatal tolerance has been recognized, little of the actual mechanism has been elucidated. In the past decade a correlation between the establishment of neonatal tolerance and immune deviation (a shift from Th1 to Th2 responses) has been observed (4, 5, 7, 14). However, whether the resulting immune deviation is a cause or an effect of neonatal tolerance was not clear. In this report we have used Stat4-deficient and Stat6-deficient mice, which have defects in Th1 and Th2 development, respectively, to test the importance of immune deviation in tolerance establishment. We found that tolerance is efficiently established in wild-type, Stat4-deficient, and Stat6-deficient mice regardless of immune deviation. Thus, activation of cells other than Stat6-dependent Th2 cells is responsible for the tolerant state when neonates are exposed to Ag.

Previous studies have noted that administration of IL-12, IFN-{gamma}, or anti-IL-4 at the time of neonatal exposure to alloantigen abrogates the tolerant state (10, 11, 12, 13). This was taken to support the concept of immune deviation in neonatal tolerance. Indeed, recent evidence suggests that mice deficient in IL-4 and IL-13, but not IL-4 alone, cannot develop tolerance (51). This report did not examine T cell proliferative or Ab responses, but demonstrated graft rejection in IL-4/IL-13 double-deficient mice that had been tolerized as neonates. Importantly, both IL-4 and IL-13 may activate signaling pathways other than Stat6. These distinct pathways may be important for tolerance and account for the difference between the phenotype of cytokine-deficient and Stat6-deficient mice. Furthermore, IL-4 and IFN-{gamma} may have reciprocal effects on many T cell subsets. Indeed, IFN-{gamma} inhibits, and IL-4 enhances, the development of TGF-{beta}-secreting Th3 cells (52). Thus, the presence or the absence of Th1- and Th2-polarizing cytokines during the induction of neonatal tolerance may have profound effects on the immune system distinct from a shift from Th1 to Th2 responses.

The cell populations that are responsible for neonatal tolerance are still elusive. It is still possible that Stat6-independent Th2 cells may play some role in this process. Furthermore, several other T cell subsets have been implicated in immunoregulatory responses. We have examined the in vitro differentiation of Tr1 cells (53, 54) and found that Stat6-deficient T cell cultures have greatly decreased numbers of IL-10-secreting cells compared with wild-type or Stat4-deficient T cell cultures (our unpublished observations). Thus, Tr1 cells seem unlikely candidates for regulating this response. We have also examined the development of Th3 cells in vitro and found that while all three genotypes can develop T cells secreting TGF-{beta}, levels are lower (by ~50%) in Stat6-deficient cultures. This correlates with the reported ability of IL-4 to promote TGF-{beta} secretion and observed decreased TGF-{beta} in T. cruzi-infected, Stat6-deficient mice (22, 52). The biological significance of this decrease is unclear, since both Stat4- and Stat6-deficient mice can be orally tolerized (55). Whether these T cell subsets or other functional subsets are required for neonatal tolerance will require further examination.

One somewhat surprising aspect of our results was the lack of an Ag-specific IgG1 response in tolerized mice. Forsthuber et al. (5) demonstrate increased levels of anti-HEL IgG1 and decreased IgG2a in mice that were tolerized as neonates. However, the adult challenge to examine Ab levels in that study used HEL in saline, not CFA as in our study. Maverakis et al. (50) observed unchanged levels of anti-HEL IgG1 with decreased IgG2a in a similar model of neonatal tolerance. The adult challenge in that study used HEL emulsified in CFA as we did, but their challenge was by footpad injection, while ours was by s.c. injection. Thus, it is not clear whether the site of administration or the presence or the absence of adjuvant during challenge may explain these differing results. However, it is clear that there is no consensus on the effects of neonatal tolerance on Ag-specific IgG1 levels.

STAT proteins have become intriguing targets for drug discovery because they play critical roles in many responses. The established roles of Stat4 in inflammatory disease and of Stat6 in allergic disease suggest these pathways as important mediators of in vivo immunity. However, Stat4 and Stat6 have been shown to have relatively minor roles in oral tolerance (55) and, as we have shown here, neonatal tolerance. Thus, these studies alter the paradigm of elements required for neonatal tolerance and provide a starting point for further dissection of the components necessary for the establishment of tolerance.


   Acknowledgments
 
We thank Janice Blum for review of this manuscript, and Heather Bruns for Ig standards.


   Footnotes
 
1 This work was supported by a grant-in-aid from the American Heart Association, an award from the Showalter Trust, and National Institutes of Health Grant AI45515 (to M.H.K.). H.-C.C. was supported by National Institutes of Health Training Grant T32DK007519. Back

2 Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Microbiology and Immunology, Walther Oncology Center, 1044 West Walnut Street, Room 302, Indianapolis, IN 46202. E-mail address: mkaplan2{at}iupui.edu Back

3 Abbreviations used in this paper: HEL, hen egg lysozyme; SI, stimulation index. Back

Received for publication June 11, 2002. Accepted for publication August 5, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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