ANTIGEN PRESENTATION BY HUMAN FETAL ASTROCYTES WITH THE COOPERATIVE EFFECT OF MICROGLIA OR THE MICROGLIAL-DERIVED CYTOKINE IL-1

Antigen presentation by endogenous glial cells is postulated to regula te reactivity of immune cells that gain entry into the CNS. We have pr eviously observed, using a mixed lymphocyte reaction (MLR) system, tha t adult human-derived microglia can function as antigen-presenting cel ls (APC) for immediately ex vivo CD4(+) T cells in a primary MLR (1 de grees MLR) whereas astrocytes could not. We have now found that fetal human astrocytes can support CD4(+) T cell proliferation in the presen ce of exogenous human recombinant (r) IL-2, and that astrocytes can su pport the continued proliferation of CD4(+) T cells previously sensiti zed to sister astrocyte cultures in a secondary MLR (2 degrees MLR). A dditionally, adult human microglia, seeded into the nonpriming astrocy te: CD4(+) T cell cocultures at non-T cell-stimulatory concentrations of 1000-5000 microglial cells per well, could reverse the inability of astrocytes to present antigen in the 1 degrees MLR. To examine the ce llular basis for the inability of human astrocytes to function as APCs in the 1 degrees MLR, astrocyte- and microglial-enriched populations were established from human embryonic and adult brain, respectively, a nd analyzed for their ability to synthesize cytokines potentially rele vant as accessory signals in the MLR. Microglia had transcript as dete rmined by the reverse transcriptase-polymerase chain reaction (RT-PCR) and protein as determined by bioassay for IL-1 alpha, IL-6, and TNF a lpha. Human fetal astrocytes had transcript for IL-6 but not for IL-1 alpha or TNF alpha under basal culture conditions and following IFN ga mma stimulation. The addition of human rIL-1 from 1-50 U/ml could reve rse the inability of astrocytes to present antigen in the primary MLR. These studies demonstrate that although in vitro highly enriched cult ures of astrocytes absent of microglia cannot present antigen to immed iately ex vivo blood-derived CD4(+) T cells in the MLR, in situ, with the cooperative help of microglia-derived cytokines or accessory surfa ce molecules, astrocytes may function as central nervous system APCs.