RESTING AND ANERGIC B-CELLS ARE DEFECTIVE IN CD28-DEPENDENT COSTIMULATION OF NAIVE CD4(-CELLS() T)

Successful antibody production in vivo depends on a number of cellular events, one of the most important of these being cognate B cell-T cel l interaction. To examine this phenomenon in vitro, homogeneous popula tions of hen egg lysozyme (HEL)-specific small resting B cells and nai ve CD4(+) HEL-specific T cells (derived from immunoglobulin [Ig] and T cell receptor transgenic mice, respectively) were cultured together. On addition of intact HEL protein, HEL-specific B cells increase their expression of activation molecules, including a B7-related protein an d CD44, and enlarge into blast cells. Within the same cultures, HEL-sp ecific CD4(+) T cells also increase expression of the activation marke rs CD69 and CD44, enlarge, secrete lymphokines, and proliferate. This response is radiation sensitive, supporting the conclusion that HEL-sp ecific B cells present antigen to and activate the naive T cells. By c ontrast, when a synthetic peptide fragment of HEL is used to bypass B cell antigen-receptor engagement, the naive T cells enlarge and displa y activation antigens, but fail to produce lymphokines, proliferate, o r promote B cell blastogenesis. Presentation of HEL by tolerant B cell s, which are no longer able to signal effectively through their antige n receptors, results in an identical pattern of incomplete T cell acti vation. Addition of a stimulating anti-CD28 antibody and blocking of C D28 signals with CTLA4/Ig fusion protein both show that complete activ ation of naive CD4(+) T cells depends on the initial induction of B7 a nd related costimulatory molecules after HEL binding to nontolerant HE L-specific B cells. Thus, in the absence of adequate costimulation fro m the B cell, naive CD4(+) T cells undergo a form of ''partial activat ion'' in which they upregulate surface expression of certain T cell ac tivation antigens, but fail to efficiently produce lymphokine and prol iferate. This may explain the different conclusions that have been rea ched regarding the consequences of B cell antigen presentation to T ce lls, in that the ability of B cells to activate naive CD4(+) T cells d epends both on their specificity and their activation state.