Persistence of anti‐donor allohelper T cells after neonatal induction of allotolerance in mice

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Abstract
BALB/c mice rendered tolerant to A/J alloantigens by neonatal injection of 108 (A/J × BALB/c)F1 spleen cells develop an autoimmune disease associated with a polyclonal activation of donor B cells. To study the mechanisms leading to donor B cell activation in tolerant mice, we prepared mixed lymphocyte cultures (MLC) between splenic T cells from neonatally injected mice and donor‐type (A/J × BALB/c)F1 or third‐party (C57BL/6 × BALB/c)F1 B cells. T cells from tolerized mice were unable to generate cytotoxic T lymphocytes, to proliferate or to secrete interleukin (IL)2 after stimulation with donor alloantigens in MLC. These T cell responses were present after MLC with third‐party antigens, but were of lower intensity than those generated by control BALB/c T cells. In contrast. T cells from tolerized mice stimulated immunoglobulin production by donor‐type (A/J × BALB/c)F1 B cells much more powerfully than T cells from control BALB/c mice. The stimulation of donor‐type (A/J × BALB/c)F1 B cells was polyclonal, as attested by the levels of anti‐hapten and anti‐DNA antibodies in the MLC supernatants. IgM was the dominant isotype secreted in vitro, but IgG1 and IgG3 were also produced in significant amounts. Lysis experiments indicated that the T cells responsible for F1 B cell stimulation in MLC were CD4+ host T cells. These T helper cells were alloreactive since they did not stimulate syngeneic BALB/c B cells, and their effect on donor B cells was specifically blocked by anti‐donor Ia monoclonal antibodies. Addition of anti‐IL 4 monoclonal antibody to MLC between T cells from tolerant mice and (A/J × BALB/c)F1 B cells almost completely abolished the production of IgG1, but not that of IgM or IgG3. Taken together, these findings indicate that neonatal injection of alloantigens in BALB/c mice induces a state of dissociated tolerance, with unresponsiveness of anti‐donor T cells secreting IL 2 on the one hand, and persistence of T cells responsible for B cell help and IL 4 secretion on the other hand.