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L-Selectin-Specific Autoantibodies in Murine Lupus: Possible Involvement in Abnormal Homing and Polarization of CD4⁺ T Cell Subsets¹

Susumu Hattori^*, Hiroyuki Nishimura^*,, Hiromichi Tsurui^*, Masayuki Kato, Naoki Endo, Masaaki Abe^*, Shin Akakura^*, Kenichi Mitsui^*, Sho Ishikawa^*, Sachiko Hirose^* and Toshikazu Shirai^2,*

^* Department of Pathology, Juntendo University School of Medicine, Hongo Bunkyo-ku, Tokyo, Japan; and Toin Human Science and Technology Center, Toin University of Yokohama, Kurogane-cho, Aoba-ku, Yokohama.

One notable functional abnormality in murine and human systemic lupus erythematosus (SLE) is the defect in the production of IL-2 in association with the deficit in naive CD4⁺ T cells. The mechanism is unknown, but one idea is that naturally occurring autoantibodies with specificities to the naive CD4⁺ T cell subpopulation are related to this event. We selected hybridoma monoclonal autoantibodies from SLE-prone (New Zealand Black (NZB) x New Zealand White (NZW))F₁ mice that reacted with restricted populations of CD4⁺ T cells. One of these, H32, was specific for L-selectin, as determined by 1) distribution of Ag H32 on lymphoid cells similar to Mel-14, an epitope of L-selectin; 2) shedding of 80-kDa molecules with epitope H32 from the surface of lymph node cells coincidentally with Mel-14, when stimulated with phorbol ester; 3) cross-inhibitory activities on Ag binding between H32 and Mel-14; and 4) reactivity of H32 with recombinant mouse L-selectin. Pretreatment of ⁵¹Cr-labeled lymphocytes from BALB/c mice with H32 significantly inhibited their homing to lymph nodes in vivo. The BALB/c splenic H32⁺ CD4⁺ T cell subset produced few cytokines except IL-2, thus corresponding to naive ThP-type cells. This subset was markedly selectively depleted in aged (NZB x NZW)F₁ mice. There was an age-associated increase in frequencies and titers of anti-L-selectin autoantibodies in sera from (NZB x NZW)F₁ mice. Thus, abnormalities of naive CD4⁺ T cell subset, including IL-2 production in subjects with SLE, are at least partly attributed to the generation of autoantibodies to L-selectin.