Mature B cells undergo programmed cell death when surface (s) Ig is extensively multimerized. A signal that blocks death of B cells is thus required for activation of B cells in response to antigen stimulation. Here we show that only a few diverse transmembrane signals capable of inducing activation and proliferation of B cells blocked sig-mediated death of normal mature B cells, and that there is no correlation between mitogenic activity and the ability to rescue B cells from death. The results suggest that a specific signal is required for abrogating B cell death induced by sig cross-linking. Signaling via IL-4 receptor and CD40, both of which are derived from activated T cells, blocked sig-mediated death, as described previously. Signaling through a B cell antigen CD72, a counter-receptor of the pan-T antigen CD5, also blocked death of anti-Ig-treated mouse spleen B cells. CD72 signal may play a role in survival of B cells at the initial step of T-B interaction, where resting T cells recognize antigens presented by B cells. Moreover, B cell death by anti-Ig was blocked by T cell-independent antigens such as lipopolysaccharide and dextran sulfate, and spleen B cells from New Zealand mice, which are prone to autoantibody-dependent autoimmune diseases, were resistant to sig-mediated death. Mechanisms for blocking sig-mediated death may therefore be required in antibody response to foreign antigens regardless of T independence or T dependence and in autoantibody production.

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Mice homozygous for either of two autosomal recessive mutations, lpr and gld, develop massive, generalized lymphoproliferation of CD4-CD8- (double negative, DN) T cells associated with a variety of autoantibodies. To determine the origin of these expanded populations of lpr and gld T cells, we examined the expression of CD2 molecules and mRNA transcripts in association with other cell surface phenotypes of these cells and correlated them with subpopulations of DN T cells in the thymus and peripheral lymphoid tissues. The results indicated that both lpr and gld cells are negative for the transcript and product of the CD2 gene. Both lpr and gld DN T cells were CD2-, CD3+, CD4-, CD8-, CD25-, CD45R+, TCR alpha/beta+, TCR gamma/delta-, HSA(J11d)-/+, Thy-1+/-, and Lp-1-/+. Studies of thymocytes in normal mice using three-color flow cytometry analysis showed that there are at least eight phenotypically distinct populations of DN thymocytes, one of which is similar to lpr and gld cells in terms of CD2-, CD3+, TCR alpha/beta+ and CD25- phenotypes, although they did not express CD45R, HSA, or Lp-1. A very minor population of these CD2-CD3+ TCR alpha/beta+ DN T cells were also detected in peripheral T cells from normal mice. These findings may provide insight into not only the origin of the aberrant lpr and gld T cells but also normal T cell development.

In chronic hepatitis C, Fas expression is up-regulated in the hepatocytes, especially near liver-infiltrating lymphocytes, and Fas ligand is expressed on the lymphocytes. The presence of hepatitis C virus (HCV)-specific CTLs has been demonstrated both in peripheral blood and among liver-infiltrating lymphocytes of patients with chronic hepatitis C. We studied the killing mechanisms of HCV-specific human CTLs using target cells that were sensitive or resistant to agonistic anti-Fas Abs and TNF-alpha. We show that HCV-specific CTL clones kill non-Ag-bearing bystander cells as well as Ag-bearing cells, although the bystander killing is less efficient than the specific target cell killing, and the efficacy of the bystander killing of anti-Fas- and soluble TNF-alpha-sensitive cells is greater than that of resistant cells. We also show that the killing of Ag-presenting, sensitive cells is mediated by Fas ligand and TNF-alpha as well as perforin, although the latter plays a major role in the killing at a low E:T ratio, and that the killing of sensitive bystander cells is primarily mediated by Fas ligand and TNF-alpha on CTLs expressed upon specific Ag stimulation, which may be relevant to the bystander lysis by HCV-specific CTLs of uninfected hepatocytes, in which Fas expression is up-regulated. Activated CTLs also kill bystander cells by the perforin-based mechanism, although it requires a high E:T ratio. The effective bystander killing requires a close intercellular contact between CTLs and target cells, although TNF-alpha released from the CTLs mediates lysis of the bystander cells without a close cell-cell contact.

SUMMARYActivated human and rat T cells as well as mouse T-cell clones have been reported to synthesize and express major histocompatibility complex (MHC) class II molecules. However, the capacity of class II antigen (Ag) presenting T cells to induce proliferation of Ag-specific cloned T cells has been controversial. We analysed whether the failure of some T-cell clones to proliferate in response to Ag presented by class II T cells is because of a lack of costimulatory cytokine production by the antigenpresenting cells (APC). As a model system the mouse class II cloned BI/O4.1 T cells were used as APC in order to activate the T cell clone KIII5. This T-helper 1 (Th1) type, GAT (synthetic copolymer of Lglutamic acid, L-alanine and L-tyrosine)-specific clone is characterized by an efficient downregulation of interleukin-2 receptor (IL-2R) with time following antigenic stimulation. KIII5 cells respond to GATpresenting splenic antigen-presenting cells (APC) by IL-2 production, IL-2R upregulation and proliferation. When BI/O4.1 T cells were used as APC, KIII5 cells produced IL-2, but did not proliferate. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a lack of IL-12 production by BI/O4.1 cells. Addition of IL-12 to a coculture of Ag-presenting BI/O4.1 cells and KIII5 cells fully reconstituted a proliferative response. IL-12 in synergy with IL-2 upregulated IL-2Ra chain expression and enhanced proliferation of KIII5 cells. Our data suggest, that class II T cells are not functional in inducing Ag-mediated expansion of resting Th1 cells owing to their failure to produce IL-12, but rather that they play a role in amplification loops during an ongoing immune response.