Reduced expression of interleukin-2 decreases the frequency of alopecia areata onset in C3H/HeJ mice

Alopecia areata (AA) is an autoimmune hair loss disease, that can be transferred between C3H/HeJ mice by skin grafting. We explored whether AA susceptibility is influenced by the availability of interleukin (IL)-2, a cytokine with leukocyte activating and regulatory properties. Mice heterozygous for a targeted deletion of IL-2 from the histocompatible C3.129P2(B6)-II2(tm1Hor) substrain, that produce reduced levels of IL-2, were examined for AA development after grafting skin from AA-affected C3H/HeJ mice. After grafting, nine of 19 (47%) heterozygous IL-2(+/-) versus 16 of 18 (88%) IL-2(+/+) wild-type littermates developed AA. Although dense follicular leukocyte infiltrates were apparent in AA affected wild-type mice, AA-developing IL-2(+/-) littermates had a reduced leukocyte infiltration, and AA-resistant IL-2 mice had no inflammation. Lymph node cell analysis revealed a reduction in leukocyte activation markers in AA-developing IL-2(+/-) mice. IL-2(+/-) mice presented with low level expression of cytokines (IL-4, IL-10, interferon-gamma, transforming growth factor-beta), upregulation of tumor necrosis factor receptors, and increased leukocyte apoptosis susceptibility independent of AA expression. In the skin, CD4(+) cells and monocytes were reduced; activation markers were not upregulated and very few CD44v3(+) or CD44v10(+) leukocytes were recovered. Taken together, our data suggest that AA resistance of IL-2(+/-) mice is because of the failure of activated leukocyte recruitment, thus pointing toward an involvement of IL-2 in AA pathogenesis.