Interaction between CD4 Th cells and bone marrow allergic progenitor cells

Th2 immunity, once established, can exert a broad influence on many cell types to form a network of effector cells, including Th2 cytokine-producing basophils, mast cells and eosinophils. However, how Th2 cells communicate with bone marrow progenitors cells to further enhance type-2 immune responses has not been explored extensively. We are exmaning three possible mechanisms. First, circulating Th2 cytokines can enter the bone marrow to exert their biological activities directly on various hematopoietic progenitors. Second, bone marrow progenitors can be recruited into the lung, where they undergo maturation and expansion. Finally, memory Th2 cells can enter the blood stream and reside in the bone marrow.

While we haven’t obtained direct evidence to support the first possiblity (Th2 cytokines can circulate into the bone marrow), we have demonstrated that Th2 cytokines, such as IL-3, IL-4, and IL-5, can direct bone marrow progenitors to differentiate eosinophils and basophils that can produce Th2 cytokines (Zhu, JI, 2004). We found that IL-3 can induce dramatic expansion of i2GMPs and basophil lineage-restricted progenitors in vivo (Ohmori, JI 2009). We demonstrated that IL-5 drives bone marrow progenitor cells primarily to differentiate into Th2 cytokine-producing eosinophils dependent upon STAT5 (Zhu, JI Cutting edge) and transcription factor GATA1. Currently, we are using GATA1 mutants to determine how GATA1 regulates the Il4 gene in eosinophils. Currently, we are testing the above-mentioned second possibility.

In summary, we have found a niche that defines our lab. In that niche we will be productive for many years to come.

 

References

  1. Zhang Y, Apilado R, Coleman J, Ben-Sasson S, Tsang S, Hu-Li J, Paul WE, Huang H. Interferon gamma stabilizes the T helper cell type 1 phenotype. J Exp Med. 2001 Jul 16;194(2):165-72.
  2. Huang Z, Xin J, Coleman J, Huang H. IFN-gamma suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor. J Immunol. 2005 Feb 1;174 (3):1332-7.
  3. Zhuang Y, Huang Z, Nishida J, Brown M, Zhang L, Huang H. A continuous T-bet expression is required to silence the interleukin-4-producing potential in T helper type 1 cells. Immunology. 2009 Sep;128(1):34-42.
  4. Zhuang Y, Huang Z, Nishida J, Zhang L, Huang H. Signaling pathways that lead to the silencing of the interleukin-4-producing potential in Th1 cells. J Interferon Cytokine Res. 2009 Jul;29(7):399-406.
  5. Zhu Y, Chen L, Huang Z, Alkan S, Bunting KD, Wen R, Wang D, Huang H. Cutting edge: IL-5 primes Th2 cytokine-producing capacity in eosinophil’s through a STAT5-dependent mechanism. J Immunol. 2004 Sep 1;173(5):2918-22.
  6. Qi X, Nishida J, Chaves L, Ohmori K, Huang H. CCAAT/enhancer-binding     protein alpha (C/EBPalpha) is critical for interleukin-4 expression in response to FcepsilonRI receptor cross-linking. J Biol Chem. 2011 May 6;286(18):16063-73. Epub 2011 Mar 21.
  7. Ohmori K, Luo Y, Jia Y, Nishida J, Wang Z, Bunting KD, Wang D, Huang H. IL-3 induces basophil expansion in vivo by directing granulocyte-monocyte progenitors to differentiate into basophil lineage-restricted progenitors in the bone marrow and by increasing the number of basophil/mast cell progenitors in the spleen. JImmunol. 2009 Mar 1;182(5):2835-41.
  8. Huang H. Suppressing allergic immune responses. Front Biosci (Elite Ed). 2011 Jun 1;3:864-70
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