Immune Netw.  2010 Jun;10(3):104-108. 10.4110/in.2010.10.3.104.

Agonistic Anti-CD137 Monoclonal Antibody Treatment Induces CD11b+Gr-1+ Myeloid-derived Suppressor Cells

• Lee JM
• Seo JH
• Kim YJ
• Kim YS
• Ko HJ
• Kang CY

• KMID: 2150667
• DOI: http://doi.org/10.4110/in.2010.10.3.104

Abstract

CD137 (4-1BB/tnfrsf9) has been shown to co-stimulate T cells. However, agonistic anti-CD137 monoclonal antibody (mAb) treatment can suppress CD4+ T cells, ameliorating autoimmune diseases, whereas it induces activation of CD8+ T cells, resulting in diverse therapeutic activity in cancer, viral infection. To investigate the CD137-mediated T cell suppression mechanism, we examined whether anti-CD137 mAb treatment could affect CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). Intriguingly, anti-CD137 mAb injection significantly increased CD11b+Gr-1+ cells, peaking at days 5 to 10 and continuing for at least 25 days. Furthermore, this cell population could suppress both CD8+ T cells and CD4+ T cells. Thus, this study demonstrated that, for the first time, anti-CD137 mAb treatment could induce CD11b+Gr-1+ MDSCs under normal conditions, suggesting a possible relationship between myeloid cell induction and CD137-mediated immune suppression.

Keyword

CD137; CD11b+Gr-1+ cells; Myeloid-derived suppressor cells; Immunosuppression

MeSH Terms

Autoimmune Diseases
Immunosuppression
Myeloid Cells
T-Lymphocytes

Figure

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  Figure 1 Agonistic anti-CD137 Ab treatment increases CD11b+Gr-1+ cells in spleen. Naïve BALB/c mice were intraperitoneally (i.p) injected with 300µg of anti-CD137 Ab (3H3) or rIgG control Ab. Five days later, the percentage (A) and number (B) of CD8+ T cells (CD3ε-CD8α+), CD4+ T cells (CD3ε-CD4+), B cells (B220+CD3ε-), NK cells (CD49b+CD3ε-), CD11c+CD8α+ cells and CD11b+Gr-1+ cells in splenocytes were examined (n=3~4/group). *p<0.05, **p<0.005, †p<0.001. Data are representative of at least three separate experiments.

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  Figure 2 The kinetics of splenic CD11b+Gr-1+ cells due to anti-CD137 Ab treatment. The kinetic changes in percentage (A) and number (B) of splenic CD11b+Gr-1+ cells were measured after 300µg of anti-CD137 Ab i.p injection.

• 

  Figure 3 Increased xCD11b+Gr-1+ cells by CD137 stimulation suppress T cell proliferation. Total splenocytes (4×105) of DO11.10 mice (A, C) or OT-I mice (B, D) were stimulated with OVA protein (A, C: 100µg/ml, B, D: 250µg/ml) and serially diluted naïve splenic CD11b+Gr-1+ cells or 3H3 induced CD11b+Gr-1+ cells (A, B: 5 days after 3H3 treatment; C, D: 25 days after 3H3 treatment) were added. Three days after culture, T cell proliferation was examined including an 18 hr pulse with 4µCi/ml [3H] thymidine.

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