ALPHA-BETA-T-CELL REGULATION AND CD40 LIGAND DEPENDENCE IN MURINE SYSTEMIC AUTOIMMUNITY

To explore the mechanisms by which alpha beta T cells and gamma delta T cells regulate systemic autoimmunity, lupus-prone mice were rendered deficient in CD40 ligand and/or alpha beta T cells by intercrossing C D40L -/- and TCR-alpha -/- knockouts, generating CD40L-intact or -defi cient (CD40L(+) or CD40L(-)), alpha beta T cell-intact or -deficient ( alpha beta(+) or alpha beta(-)) MRL-lpr/lpr animals. As expected, CD40 L(+) alpha beta(+) mice developed high titer autoantibodies along with severe renal and cutaneous disease, CD40L(+)alpha beta(-) animals dev eloped lower levels of autoantibodies, accompanied by less severe or d elayed renal and cutaneous disease, CD40L(-)alpha beta(+) mice develop ed even lower titers of autoantibodies and less severe renal disease y et developed cutaneous lesions indistinguishable from those of CD40L()alpha beta(+) disease, Most surprisingly, CD40L(-)alpha beta(-) anima ls developed higher levels of some autoantibodies than did CD40L(-)alp ha beta(+) mice and developed renal disease similar in severity to CD4 0L(+)alpha beta(-) counterparts; however, they failed to develop skin disease, Thus, disruption of CD40L and alpha beta T cells provides a n ovel dissection of the physiology and pathology of murine lupus; while these data confirm previous findings demonstrating a role for CD40L-d ependent, alpha beta T cell-dependent mechanisms in autoantibody produ ction and renal disease in murine lupus, they also: i) establish that alpha beta T cells may drive autoimmune skin disease by a CD40L-indepe ndent mechanism; 2) identify a role for CD40L in non-alpha beta T cell -dependent autoantibody production and autoimmune skin disease; and 3) suggest a role for alpha beta T cells in the down-regulation of autoi mmunity driven by other T cells. Thus, both alpha beta and non-alpha b eta T cells, such as gamma delta T cells, regulate systemic autoimmuni ty by CD40L-dependent and -independent mechanisms.