Constitutively active STAT6 predisposes toward a lymphoproliferative disorder

Abstract

Signal transducer and activator of transcription 6 (STAT6) is critical for IL-4 and IL-13 responses, and necessary for the normal development of Th2 cells. We previously generated mice that express a constitutively active STAT6 (STAT6VT) under control of the CD2 locus control region, which directs expression to the T-cell compartment. We now describe that a small proportion of these mice (~5%) develop a spontaneous lymphoproliferative disease (LPD) that results in dramatic splenomegaly. The cell populations observed in the LPD spleens can be divided into 2 categories, those that are composed of mixed lineage cells and those that are predominantly T cells with a phenotype similar to that in autoimmune lymphoproliferative syndrome (ALPS) patients. These data suggest that while active STAT6 is not a transforming factor, expression in T cells predisposes toward the development of lymphoproliferative disorders.

Figure 1

Lymphoproliferative disease in Stat6VT transgenic mice (A) Photograph of mouse with lymphoproliferative disease. Spleen is extended through entire peritoneum (). Lymphadenopathy is also apparent. (B) Comparison of spleen size from wild-type mouse (bottom left) compared with spleen from mouse with LPD. (C) Flow cytometric analysis of splenocytes from wild type, Stat6VT transgenic and 2 Stat6VT transgenic mice with LPD. Numbers in quadrants represent percentage of total spleen cells. Average latency (the age of the mouse, in days, at which the LPD was characterized) and averages of spleen cell numbers (range shown in brackets) are shown below (n = 11 for class A and n = 10 for class B).

Figure 2

T-cell expansion in class A LPD mice. (A) FACS analysis of spleen cells from wild type mice and 2 Stat6VT transgenic mice with class A LPD. Data are shown for staining of 2 TCR Vβ regions on the ordinate. Samples were counterstained for CD3 on the abscissa. Numbers on plots represent percentage of total spleen cells. (B) Total splenocytes from mice of the indicated genotypes were fixed and stained with propidium iodide to analyze DNA content. Numbers shown are the percentages of CD3⁺cells that are in S + G2/M phases of the cell cycle. (C) Isolated splenocytes from wild type or Stat6VT transgenic mice or 2 mice with class A LPD were incubated in 96-well plates and proliferation was assessed using uptake of ³H-thymidine. (D) CD3⁺ splenocytes from mice of the indicated genotypes were tested for propidium iodide exclusion as a measure of apoptosis.