Resistance and susceptibility of neural cells to lysis by cytotoxic lymphocytes and by cytolytic granules

The susceptibility of neural cells to immune-mediated lysis by alloantigen-specific cytotoxic lymphocytes is important in understanding cell-mediated immune responses during rejection of transplanted neural tissues and in inflammatory responses of the central (CNS) and peripheral (PNS) nervous systems. In this study, we used 51Cr-release and granzyme A assays to examine whether primary cultures of astrocytes and CNS and PNS neurons could serve as targets for alloantigen-specific CTLs and granule-mediated lysis. The level of astrocyte killing by alloantigen-specific CTLs correlated with expression of the class I gene products of the major histocompatibility complex. Astrocytes cultured for 1-2 weeks did not express class I MHC antigens and were not susceptible to lysis by activated alloantigen-specific CTLs. Lengthening the astrocyte culture period to 3 weeks resulted in class I MHC antigen expression on the astrocyte surface and alloantigen-specific lysis. Astrocytes of all ages tested were susceptible to lysis by isolated cytolytic lymphocyte granules. PNS neurons of various ages tested also served as targets for CTLs and were lysed by isolated granules. In contrast, CNS neurons did not express class I MHC antigens and were highly resistant to killing by CTLs and lymphocyte granules. CNS neurons and astrocytes did not trigger specific granzyme A secretion from effector cells. In the presence of leucoagglutinin, CTLs-specific recognition of target cells is bypassed, and virtually any cell, regardless of its antigens, is killed nonspecifically. Although leucoagglutinin-treated CNS neurons and astrocytes triggered increased granzyme A secretion from effector cells, only astrocytes were lysed in an antigen-nonspecific manner, whereas CNS neurons remained strikingly resistant. These results suggest differences in the susceptibility of PNS and CNS neurons to T cell-mediated lysis. CNS neurons appear to possess protective mechanisms that render them refractory to CTL-mediated lysis and granule-mediated lysis, whereas PNS neurons and astrocytes are far more susceptible to both types of immune attack.