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The Journal of Immunology, 2002, 168: 991-995.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Inducible Costimulator Protein Regulates Both Th1 and Th2 Responses to Cutaneous Leishmaniasis1

Rebecca J. Greenwald*, Alexander J. McAdam*,{dagger}, Diane Van der Woude*, Abhay R. Satoskar{ddagger} and Arlene H. Sharpe2,*

* Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; {dagger} Department of Laboratory Medicine, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115; and {ddagger} Department of Microbiology, Ohio State University, Columbus, OH 43210


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The CD28 family member inducible costimulator protein (ICOS) has an important role in T cell differentiation and Ig class switching. To investigate the role of ICOS in vivo, ICOS-/- mice were infected s.c. with Leishmania mexicana. While wild-type mice developed large, cutaneous lesions, the growth of lesions and tissue histopathology was significantly delayed in ICOS-/- mice. ICOS-/- mice exhibited marked decreases in both Th1 and Th2 cytokine production and profound defects in L. mexicana-specific Ig isotype class switching to IgG1 and IgG2a and reduced total IgE levels. Our findings indicate that ICOS is a key regulator of both Th1 and Th2 responses and has a role in controlling cutaneous L. mexicana infection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Two signals are required for optimal activation of T cells. The first signal is provided by the engagement of the TCR with the MHC-peptide complex on APCs, and the second signal is delivered by costimulatory molecules. Although the B7:CD28/CTLA-4 costimulatory pathway is pivotal in T cell activation, other costimulatory pathways may be critical in Th cell differentiation. The homolog of CD28, inducible costimulator protein (ICOS),3 provides important costimulatory signals to T cells (1, 2, 3). ICOS enhances T cell cytokine production, up-regulation of CD40 ligand, and help for Ig production by B cells (1, 4).

There are several features of ICOS that distinguish it from CD28. While CD28 is constitutively expressed on most T cells, ICOS is induced upon TCR engagement. Expression of ICOS is enhanced by CD28 costimulation (4). In contrast to CD28 and CTLA-4, ICOS does not bind B7-1 or B7-2 (1). The ligand for ICOS is B7h (GL50, B7RP-1, LICOS, B7H2), which is expressed on APCs as well as other cell types (5, 6, 7).

The importance of the ICOS:B7h pathway in vivo is only beginning to be appreciated (2, 3, 8). The inducible expression of ICOS suggests that ICOS regulates recently activated and effector T cell responses. Functional studies of ICOS have suggested that ICOS is important for Th2 immune responses, preferentially inducing IL-4 and IL-10 production (3, 4, 9, 10, 11). The role of ICOS in Th2 responses has been demonstrated in studies of allergic airway disease. The most profound effects on Th2 cytokine production were observed when ICOS was blocked during airway challenge in primed mice (11). ICOS-/- mice were susceptible to induction of inflammatory lung disease induced by airway challenge in primed mice, but they produced less IL-4 and IL-13 (3). Lung inflammation and airway reactivity were reduced by ICOS blockade following adoptive transfer of polarized Th2 cells to naive mice (9). These studies demonstrate a critical role for ICOS in Th2 immune responses.

However, recent studies suggest that ICOS may also regulate Th1 immune responses (12, 13, 14). Leishmania mexicana infection in mice provides a sensitive probe of Th differentiation during the immune response to infection. During L. mexicana infection, progression of lesions is determined by a balance of Th1 and Th2 responses (15). IFN-{gamma} production is required for protective host immunity after L. mexicana infection (16, 17, 18). In L. mexicana-infected IL-4-/- mice, skewing toward Th1 is observed and correlates with healing of the lesions (16). Similarly, in the absence of STAT6, a component for IL-4 signaling, mice produce high levels of IFN-{gamma} and do not develop cutaneous lesions after L. mexicana infection (15). IFN-{gamma} is a potent stimulus of macrophage NO pathways which produce leishmanicidal activity (16, 19, 20, 21). IL-4 decreases IFN-{gamma} production; thus, IL-4 production exacerbates disease by inhibiting a protective Th1 immune response.

Our studies demonstrate that L. mexicana-infected ICOS-/- mice exhibit pronounced defects in Ig class switching and T cell cytokine production. Development of cutaneous lesions and inflammatory infiltrates is impaired in ICOS-/- mice. Our findings demonstrate that ICOS is a critical regulator of both Th1 and Th2 immune responses in vivo following infection with L. mexicana.


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

Wild-type (WT) and ICOS-/- 129S4/SvJae mice were maintained in accordance with the institutional guidelines of Brigham and Women’s Hospital and Harvard Medical School (Boston, MA). Female 6- to 8-wk-old mice were used for our studies.

Infection

L. mexicana parasites (MYNC/BZ62/M379) were maintained in the rumps of BALB/c mice. Amastigotes were isolated as previously described (22). Mice were infected with 5 x 106 amastigotes of L. mexicana by s.c. injection into the rump. Lesion diameter was measured at 1-wk intervals for up to 12 wk. Lesions were examined histologically by H&E staining.

Serum ELISA

Mice were bled weekly for 12 wk after inoculation with L. mexicana. Sera were tested for total IgE and L. mexicana-specific IgM, IgG1, and IgG2a by ELISA (2). The limit of detection for IgE was 40 ng/ml.

In vitro cell preparations

Inguinal lymph nodes were collected at the indicated time following infection with L. mexicana. To measure proliferative responses and cytokine production, 5 x 105 lymph node cells were cultured in 96-well plates with 0–40 µg/ml L. mexicana freeze-thaw Ag from stationary phase promastigotes. Data reflect the mean of triplicates from each Ag concentration. Culture supernatants were collected on days 1–3 and cytokine levels were determined by ELISA (23).

Statistical significance

Student’s unpaired t test was used to determine the statistical significance of the values obtained.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The development of cutaneous lesions and tissue histopathology is delayed in ICOS-/- mice as compared with WT mice following L. mexicana infection

Following L. mexicana infection, lesions developed in WT mice as early as 3 wk; however, lesions were not detected in ICOS-/- mice until wk 4 (Fig. 1Go, A and B). At wk 6, WT mice had lesions that were 7.5 ± 0.33 mm (Fig. 1GoA), but lesions in the ICOS-/- mice were markedly reduced (2.7 ± 0.55 mm). However, by wk 12, lesion size in WT and ICOS-/- mice was similar (Fig. 1GoB). Thus, lesion development is delayed in the absence of ICOS.



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  		FIGURE 1. Cutaneous lesions and histopathology in ICOS-/- mice are reduced as compared with WT mice following L. mexicana infection. A, Lesion size was measured by mean lesion diameter in WT ({blacksquare}) and ICOS-/- ({circ}) mice following L. mexicana infection for 6 wk. *, Statistically significant differences between groups (p < 0.05). B, Progression of lesion growth was measured weekly for 12 wk following L. mexicana infection. Data are expressed as the mean ± SE. *, Statistically similar values between groups (p > 0.05). C and D, Analysis of the histopathology of skin inoculation sites from L. mexicana-infected WT and ICOS-/- mice at 6 wk postinfection. H&E-stained skin lesions from WT mice (C) showed extensive tissue damage; ICOS-/- mice (D) showed a more intact skin structure and fewer macrophages with intracellular parasites. Arrows indicate L. mexicana amastigotes. Magnification is x400. Results are representative of three experiments with four to five mice per group.

 
In WT mice, lesions had marked tissue damage with abundant eosinophils, neutrophils, and parasitized macrophages at 6 wk postinfection (Fig. 1GoC). In contrast, the inflammatory response was modest and fewer parasitized macrophages were observed in ICOS-/- mice at wk 6 (Fig. 1GoD). At 12 wk postinfection, massive inflammatory lesions and extensive tissue destruction of s.c. tissue and muscle were seen in WT mice, whereas ICOS-/- mice had much less tissue damage (data not shown). However, the nature of the inflammatory infiltrates was similar in WT and ICOS-/- mice. Thus, the development of inflammatory lesions following L. mexicana infection is delayed and less severe in ICOS-/- mice.

Ab class switching is markedly impaired in L. mexicana-infected ICOS-/- mice

Recent studies have shown that ICOS plays a critical role in Ab responses (2, 3, 8). Levels of L. mexicana-specific IgM, IgG1, and IgG2a were analyzed at 0, 2, 4, 6, and 12 wk postinfection in WT and ICOS-/- mice. At 2 wk, WT and ICOS-/- mice exhibited comparable levels of L. mexicana-specific IgM (Fig. 2GoA). High titers of L. mexicana-specific IgG2a and IgG1 were detected in WT mice at 4–12 wk (Fig. 2Go, B–E). In contrast, L. mexicana-specific IgG2a and IgG1 were at the limit of detection in ICOS-/- mice at 6 wk following infection (Fig. 2Go, B and C). At 12 wk, low levels of L. mexicana-specific IgG1 were detected in ICOS-/- mice (Fig. 2GoD). L. mexicana-specific IgG2a was not detectable in ICOS-/- mice at 12 wk postinfection (Fig. 2GoE). At 6 and 12 wk, total IgE was elevated in WT mice, but IgE was not detected in ICOS-/- mice at 6 wk and was markedly reduced at 12 wk (Fig. 3Go). Before infection, IgE in WT and ICOS-/- was below the limit of detection (data not shown). These results demonstrate that ICOS is important for Ig class switching during infection with L. mexicana.



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  		FIGURE 2. L. mexicana-specific Ig isotype class switching is defective in ICOS-/- mice at 0, 2, 4, 6, and 12 wk postinfection with L. mexicana. A, Sera were analyzed for L. mexicana-specific IgM at 2 wk postinfection. Data represent relative IgM levels for WT ({blacksquare}) and ICOS-/- ({circ}) mice at indicated serum dilutions. Values are shown for four individual mice per group and are representative of three experiments. *, Statistically similar values between groups (p > 0.05). B and C, Sera (1/50 dilution) were analyzed at 0, 2, 4, and 6 wk for L. mexicana-specific IgG2a and IgG1. Data represent the relative levels of specific IgG2a and IgG1. Values are shown for four individual mice per group for WT ({blacksquare}) and ICOS-/- ({circ}) mice. *, Statistically significant differences between groups (p < 0.05). D and E, Sera were analyzed at 12 wk for L. mexicana-specific IgG2a and IgG1. Data represent the relative levels of specific IgG2a and IgG1. Values are shown for four individual mice per group for WT ({blacksquare}) and ICOS-/- ({circ}) mice at the indicated serum dilutions. *, Statistically significant differences between groups (p < 0.05). Data are representative of three experiments.

 


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  		FIGURE 3. Defects in total IgE are observed in ICOS-/- mice at 6 and 12 wk following infection with L. mexicana. Values are shown as the mean ± SD for four to five mice per group for WT (filled bars) and ICOS-/- (open bars) mice at the indicated time. *, Statistically significant differences between groups (p < 0.05). Data are representative of three experiments.

 
Proliferative responses and cytokine production are impaired in L. mexicana-infected ICOS-/- mice

Because Ig class switching depends on Th cells, T cell responses were analyzed following infection with L. mexicana. T cell proliferation was reduced at a lower Ag concentration (4 µg/ml) in ICOS-/- mice as compared with WT mice at 6 wk (Fig. 4GoA). At 12 wk, WT and ICOS-/- mice exhibited comparable proliferative responses (Fig. 4GoB). At 6 wk postinfection, levels of IL-4 were slightly lower at day 3 in ICOS-/- mice as compared with WT mice, while IFN-{gamma} was reduced in ICOS-/- mice to 50% of WT levels (Fig. 4GoC). At 12 wk, IL-4 and IFN-{gamma} production remained low in ICOS-/--stimulated cells but was markedly elevated in WT mice (Fig. 4Go, C and D). Higher levels of IL-4 and IFN-{gamma} mRNA were detected by RNase protection assay in WT mice as compared with ICOS-/- mice from lymph nodes collected 6 and 12 wk postinfection (data not shown). Thus, ICOS promotes both Th1 and Th2 responses in vivo.



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  		FIGURE 4. Proliferative responses and IL-4 and IFN-{gamma} cytokine secretion are decreased in ICOS-/- lymph node cells as compared with WT lymph node cells following restimulation in vitro. Proliferation at 6 (A) and 12 (B) wk after infection with L. mexicana was measured from WT ({blacksquare}) and ICOS-/- ({circ}) cultures. *, Statistically similar values between groups (p > 0.05). C and D, Cytokines produced from WT ({blacksquare}) and ICOS-/- ({circ}) cultures at 6 (C) and 12 (D) wk postinfection are shown on days 1–3 of restimulation. Cells cultured in the absence of L. mexicana freeze-thaw Ag did not produce detectable IL-4 or IFN-{gamma} (data not shown). *, Values of p between groups: p > 0.05 for IL-4 and p < 0.05 for IFN-{gamma} in C; p < 0.05 for IL-4 and IFN-{gamma} in D. These results are representative of three experiments and data are expressed as the mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The outcome of L. mexicana infection in ICOS-/- mice reflects the complex interplay between Th1 and Th2 cytokines. WT mice develop nonhealing cutaneous lesions. L. mexicana-infected ICOS-/- mice exhibit impaired IL-4 and IFN-{gamma} production. The delay in disease progression reflects the low levels of IL-4 produced in the ICOS-/- mice. However, IFN-{gamma} production is also low and, in the absence of a vigorous Th1 response, cutaneous lesions on the ICOS-/- mice are not cured. Thus, the balance of Th1 and Th2 cytokines is key in determining the outcome of disease.

Our findings demonstrate that ICOS can regulate both Th1 and Th2 responses during infection to L. mexicana. Ab class switching also was impaired, consistent with a role for ICOS in both Th1 and Th2 responses, as profound defects in both Th1- and Th2-associated class switching to IgG1, IgE, and IgG2a were observed. Levels of IgM are comparable in WT and ICOS-/- mice, suggesting that B cell responsiveness is intact in the absence of ICOS. Our results are consistent with the defect in Ig class switching observed following immunization with a model protein Ag and are remarkable because parasites present a more complex challenge to the host (2). Although the defects in Ig isotype class switching persist to 12 wk in the ICOS-/- mice following L. mexicana infection, the humoral immune response is not critical for clearing of the parasitic infection. Circulating Ab promotes the internalization of L. mexicana complex amastigotes via the FcR, thus prolonging infection (24). The primary host defense mechanism for clearing L. mexicana appears to be IFN-{gamma} production.

The cross-talk between ICOS and CD28 signals is only beginning to be understood. CD28-/- mice mount effective T cell responses against several parasites (25, 26, 27, 28). The presence of highly conserved microbial structures on infectious pathogens stimulates the innate immune response via pattern recognition receptors which enhance the function of APCs and stimulate T cell responses (29). The B7h:ICOS pathway may provide distinct costimulatory signals which lead to competent T cell responses in the absence of CD28. Our results are consistent with a study showing that administration of ICOS-Ig following Nippostrongylus brasiliensis infection decreased production of both Th1 and Th2 cytokines during in vitro restimulation (30). Blockade of ICOS in the CD28-/- mice led to further reductions in cytokine production following N. brasiliensis infection, suggesting that the B7:CD28 and B7h:ICOS pathways have synergistic effects during effector T cell immune responses to infectious pathogens.

A role for ICOS in Th1 responses was not observed in models examining primary and recall responses (3). However, recent studies show a role for ICOS in Th1 responses in models of cardiac allograft survival and experimental autoimmune encephalomyelitis. Cardiac allograft rejection was delayed after ICOS blockade and was associated with reduced IFN-{gamma} and IL-10 within allografts (12). ICOS blockade during priming of experimental autoimmune encephalomyelitis exacerbates disease (increased IFN-{gamma}), but ICOS blockade during the effector phase abrogates disease (decreased IFN-{gamma}) (13). Thus, ICOS may have distinct roles during priming and effector responses that can regulate Th1- and Th2-mediated pathologies. Our studies demonstrate that ICOS can contribute to IFN-{gamma} production during a chronic infection. Thus, ICOS is a key regulator of both Th1 and Th2 responses.


   Footnotes
 
1 This work was supported by grants from the Juvenile Diabetes Foundation and the National Institutes of Health, and by an Ohio State University seed grant. Back

2 Address correspondence and reprint requests to Dr. Arlene H. Sharpe, Immunology Research Division, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115. E-mail address: asharpe{at}rics.bwh.harvard.edu Back

3 Abbreviations used in this paper: ICOS, inducible costimulator protein; WT, wild type. Back

Received for publication November 2, 2001. Accepted for publication December 10, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hutloff, A., A. M. Dittrich, K. C. Beier, B. Eljaschewitsch, R. Kraft, I. Anagnostopoulos, R. A. Kroczek. 1999. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263.[Medline]
  2. McAdam, A. J., R. J. Greenwald, M. A. Levin, T. Chernova, N. Malenkovich, V. Ling, G. J. Freeman, A. H. Sharpe. 2001. ICOS is critical for CD40-mediated antibody class switching. Nature 409:102.[Medline]
  3. Dong, C., A. E. Juedes, U. A. Temann, S. Shresta, J. P. Allison, N. H. Ruddle, R. A. Flavell. 2001. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409:97.[Medline]
  4. McAdam, A. J., T. T. Chang, A. E. Lumelsky, E. A. Greenfield, V. A. Boussiotis, J. S. Duke-Cohan, T. Chernova, N. Malenkovich, C. Jabs, V. K. Kuchroo, et al 2000. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165:5035.[Abstract/Free Full Text]
  5. Swallow, M., J. Wallin, W. Sha. 1999. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNF{alpha}. Immunity 11:423.[Medline]
  6. Yoshinaga, S. K., J. S. Whoriskey, S. D. Khare, U. Sarmiento, J. Guo, T. Horan, G. Shih, M. Zhang, M. A. Coccia, T. Kohno, et al 1999. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402:827.[Medline]
  7. Aicher, A., M. Hayden-Ledbetter, W. A. Brady, A. Pezzutto, G. Richter, D. Magaletti, S. Buckwalter, J. A. Ledbetter, E. A. Clark. 2000. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164:4689.[Abstract/Free Full Text]
  8. Tafuri, A., A. Shahinian, F. Bladt, S. K. Yoshinaga, M. Jordana, A. Wakeham, L. M. Boucher, D. Bouchard, V. S. F. Chan, G. Duncan, et al 2001. ICOS is essential for effective T-helper-cell responses. Nature 409:105.[Medline]
  9. Coyle, A. J., S. Lehar, C. Lloyd, J. Tian, T. Delaney, S. Manning, T. Nguyen, T. Burwell, H. Schneider, J. A. Gonzalo, et al 2000. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13:95.[Medline]
  10. Tesciuba, A. G., S. Subudhi, R. P. Rother, S. J. Faas, A. M. Frantz, D. Elliot, J. Weinstock, L. A. Matis, J. A. Bluestone, A. I. Sperling. 2001. Inducible costimulator regulates Th2-mediated inflammation, but not Th2 differentiation, in a model of allergic airway disease. J. Immunol. 167:1996.[Abstract/Free Full Text]
  11. Gonzalo, J. A., J. Tian, T. Delaney, J. Corcoran, J. B. Rottman, J. Lora, A. Al-garawi, R. Kroczek, J. C. Gutierrez-Ramos, A. J. Coyle. 2001. ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nat. Immunol. 2:597.[Medline]
  12. Ozkaynak, E., W. Gao, N. Shemmeri, C. Wang, J. C. Gutierrez-Ramos, J. Amaral, S. Qin, J. B. Rottman, A. J. Coyle, W. W. Hancock. 2001. Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nat. Immunol. 2:591.[Medline]
  13. Rottman, J. B., T. Smith, J. R. Tonra, K. Ganley, T. Bloom, R. Silva, B. Pierce, J. C. Gutierrez-Ramos, E. Ozkaynak, A. J. Coyle. 2001. The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. Nat. Immunol. 2:605.[Medline]
  14. Sporici, R. A., R. L. Beswick, C. von Allmen, C. A. Rumbley, M. Hayden-Ledbetter, J. A. Ledbetter, P. J. Perrin. 2001. ICOS ligand costimulation is required for T-cell encephalitogenicity. Clin. Immunol. 100:277.[Medline]
  15. Stamm, L. M., A. Raisanen-Sokolowski, M. Okano, M. E. Russell, J. R. David, A. R. Satoskar. 1998. Mice with STAT6-targeted gene disruption develop a Th1 response and control cutaneous leishmaniasis. J. Immunol. 161:6180.[Abstract/Free Full Text]
  16. Satoskar, A., H. Bluethmann, J. Alexander. 1995. Disruption of the murine interleukin-4 gene inhibits disease progression during Leishmania mexicana infection but does not increase control of Leishmania donovani infection. Infect. Immun. 63:4894.[Abstract]
  17. Afonso, L. C., P. Scott. 1993. Immune responses associated with susceptibility of C57BL/10 mice to Leishmania amazonensis. Infect. Immun. 61:2952.[Abstract/Free Full Text]
  18. Guevara-Mendoza, O., C. Une, P. Franceschi Carreira, A. Orn. 1997. Experimental infection of BALB/c mice with Leishmania panamensis and Leishmania mexicana: induction of early IFN-{gamma} but not IL-4 is associated with the development of cutaneous lesions. Scand. J. Immunol. 46:35.[Medline]
  19. Heinzel, F. P., M. D. Sadick, B. J. Holaday, R. L. Coffman, R. M. Locksley. 1989. Reciprocal expression of interferon {gamma} or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169:59.[Abstract/Free Full Text]
  20. Kopf, M., F. Brombacher, G. Kohler, G. Kienzle, K. H. Widmann, K. Lefrang, C. Humborg, B. Ledermann, W. Solbach. 1996. IL-4-deficient BALB/c mice resist infection with Leishmania major. J. Exp. Med. 184:1127.[Abstract/Free Full Text]
  21. Liew, F. Y., Y. Li, S. Millott. 1990. TNF-{alpha} synergizes with IFN-{gamma} in mediating killing of Leishmania major through the induction of nitric oxide. J. Immunol. 145:4306.[Abstract]
  22. Hart, D. T., K. Vickerman, G. H. Coombs. 1981. A quick, simple method for purifying Leishmania mexicana amastigotes in large numbers. Parasitology 82:345.[Medline]
  23. Schweitzer, A. N., F. Borriello, R. C. Wong, A. K. Abbas, A. H. Sharpe. 1997. Role of costimulators in T cell differentiation: studies using APCs lacking expression of CD80 or CD86. J. Immunol. 158:2713.[Abstract]
  24. Kima, P. E., S. L. Constant, L. Hannum, M. Colmenares, K. S. Lee, A. M. Haberman, M. J. Shlomchik, D. McMahon-Pratt. 2000. Internalization of Leishmania mexicana complex amastigotes via the Fc receptor is required to sustain infection in murine cutaneous leishmaniasis. J. Exp. Med. 191:1063.[Abstract/Free Full Text]
  25. Shahinian, A., K. Pfeffer, K. P. Lee, T. M. Kundig, K. Kishihara, A. Wakeham, K. Kawai, P. S. Ohashi, C. B. Thompson, T. W. Mak. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261:609.[Abstract/Free Full Text]
  26. Kundig, T. M., A. Shahinian, K. Kawai, H. W. Mittrucker, E. Sebzda, M. F. Bachmann, T. W. Mak, P. S. Ohashi. 1996. Duration of TCR stimulation determines costimulatory requirement of T cells. Immunity 5:41.[Medline]
  27. Brown, D. R., J. M. Green, N. H. Moskowitz, M. Davis, C. B. Thompson, S. L. Reiner. 1996. Limited role of CD28-mediated signals in T helper subset differentiation. J. Exp. Med. 184:803.[Abstract/Free Full Text]
  28. Gause, W. C., S. J. Chen, R. J. Greenwald, M. J. Halvorson, P. Lu, X. D. Zhou, S. C. Morris, K. P. Lee, C. H. June, F. D. Finkelman, et al 1997. CD28 dependence of T cell differentiation to IL-4 production varies with the particular type 2 immune response. J. Immunol. 158:4082.[Abstract]
  29. Jankovic, D., Z. Liu, W. C. Gause. 2001. Th1- and Th2-cell commitment during infectious disease: asymmetry in divergent pathways. Trends Immunol. 22:450.[Medline]
  30. Kopf, M., A. J. Coyle, N. Schmitz, M. Barner, A. Oxenius, A. Gallimore, J. C. Gutierrez-Ramos, M. F. Bachmann. 2000. Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J. Exp. Med. 192:53.[Abstract/Free Full Text]



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 J. Am. Soc. Nephrol.Home page
D. Odobasic, A. R. Kitching, T. J. Semple, and S. R. Holdsworth
Inducible Co-Stimulatory Molecule Ligand Is Protective during the Induction and Effector Phases of Crescentic Glomerulonephritis
J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1044 - 1053.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
M. Vidric, A. T. Bladt, U. Dianzani, and T. H. Watts
Role for Inducible Costimulator in Control of Salmonella enterica Serovar Typhimurium Infection in Mice
Infect. Immun., February 1, 2006; 74(2): 1050 - 1061.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. Miyamoto, C. I. Kingsley, X. Zhang, C. Jabs, L. Izikson, R. A. Sobel, H. L. Weiner, V. K. Kuchroo, and A. H. Sharpe
The ICOS Molecule Plays a Crucial Role in the Development of Mucosal Tolerance
J. Immunol., December 1, 2005; 175(11): 7341 - 7347.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B. Ruiz-Perez, D. R. Chung, A. H. Sharpe, H. Yagita, W. M. Kalka-Moll, M. H. Sayegh, D. L. Kasper, and A. O. Tzianabos
Modulation of surgical fibrosis by microbial zwitterionic polysaccharides
PNAS, November 15, 2005; 102(46): 16753 - 16758.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. Loke, X. Zang, L. Hsuan, R. Waitz, R. M. Locksley, J. E. Allen, and J. P. Allison
Inducible costimulator is required for type 2 antibody isotype switching but not T helper cell type 2 responses in chronic nematode infection
PNAS, July 12, 2005; 102(28): 9872 - 9877.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. E. A. T. van Berkel, E. H. R. Schrijver, F. M. A. Hofhuis, A. H. Sharpe, A. J. Coyle, C. P. Broeren, K. Tesselaar, and M. A. Oosterwegel
ICOS Contributes to T Cell Expansion in CTLA-4 Deficient Mice
J. Immunol., July 1, 2005; 175(1): 182 - 188.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
H. W. Murray, C. M. Lu, E. B. Brooks, R. E. Fichtl, J. L. DeVecchio, and F. P. Heinzel
Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis
Infect. Immun., November 1, 2003; 71(11): 6453 - 6462.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Yagi, Y. Arimura, U. Dianzani, T. Uede, T. Okamoto, and T. Uchiyama
Regulatory Roles of IL-2 and IL-4 in H4/Inducible Costimulator Expression on Activated CD4+ T Cells During Th Cell Development
J. Immunol., July 15, 2003; 171(2): 783 - 794.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
L. I. Rutitzky, E. Ozkaynak, J. B. Rottman, and M. J. Stadecker
Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis
Infect. Immun., July 1, 2003; 71(7): 4040 - 4044.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. Montagnoli, A. Bacci, S. Bozza, R. Gaziano, P. Mosci, A. H. Sharpe, and L. Romani
B7/CD28-Dependent CD4+CD25+ Regulatory T Cells Are Essential Components of the Memory-Protective Immunity to Candida albicans
J. Immunol., December 1, 2002; 169(11): 6298 - 6308.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
H.-W. Mittrucker, M. Kursar, A. Kohler, D. Yanagihara, S. K. Yoshinaga, and S. H. E. Kaufmann
Inducible Costimulator Protein Controls the Protective T Cell Response Against Listeria monocytogenes
J. Immunol., November 15, 2002; 169(10): 5813 - 5817.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. P. Banerjee, D. S. Vinay, A. Mathew, M. Raje, V. Parekh, D. V. R. Prasad, A. Kumar, D. Mitra, and G. C. Mishra
Evidence That Glycoprotein 96 (B2), a Stress Protein, Functions as a Th2-Specific Costimulatory Molecule
J. Immunol., October 1, 2002; 169(7): 3507 - 3518.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. N. Villegas, L. A. Lieberman, N. Mason, S. L. Blass, V. P. Zediak, R. Peach, T. Horan, S. Yoshinaga, and C. A. Hunter
A Role for Inducible Costimulator Protein in the CD28- Independent Mechanism of Resistance to Toxoplasma gondii
J. Immunol., July 15, 2002; 169(2): 937 - 943.
[Abstract] [Full Text] [PDF]

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