Cytotoxic T-cell response to ectromelia virus-infected cells. Different H-2 requirements for triggering precursor T-cell induction or lysis by effector T cells defined by the BALB/c-H-2(db) mutation

Abstract

The T(c)-cell response to ectromelia virus infection was studied in BALB/c-H-2(db) mice which carry a loss mutation in the H-2D region that results in the absence from cell surfaces of a molecule (D') bearing certain public H-2 specificities. When infected, these mice showed a poor response of T(c) cells that recognize H-2D(d) plus virus-specific determinants on infected macrophage targets, but gave a normal response to H-2K d plus virus-specific antigens. However, their own infected macrophages do display wild-type antigenic patterns involving virus and H-2D(d) since they were killed as efficiently as wild-type (BALB/c,H- 2(d))-infected cells by T(c) cells specific only for H-2D(d) plus viral antigens. When tested in vitro, infected BALB/c-H-2(db) cells stimulated a poor T(c)-cell response to H-2D plus virus-specific antigens, but stimulated a normal response (in comparison with infected BALB/c macrophages) to H-2K(d) plus viral antigens. Uninfected BALB/c-H-2(db) cells stimulated a normal T(c)-cell response to minor H antigens or trinitrophenyl in association with H-2D(d), thus suggesting that the defective response to infection may reside in a failure of the relevant H-2D(d) antigens of mutant cells to physically associate with viral antigens. Close association of viral and H-2D-coded molecules was also suggested by ability of specific anti-H-2K or -H-2D to partially block T(c)-cell-mediated lysis of infected targets. These results were interpreted to mean that H-2Dd-dependent, virus- immune T(c) cells recognized an antigenic pattern consisting of virus- specific and H-2D(d) determinants with the latter borne on an H-2D molecule carrying serologically-defined H-2D(d) private specificities. A second H-2D(d)-coded molecule (D') was not required for recognition and lysis by activated T(c) cells, but was apparently necessary for efficient stimulation of precursor T(c) cells, perhaps by promoting appropriate physical association of viral and H-2D(d) molecules.

TheH-2L locus and the system of H-2 specificities

“…On the one hand, the H-2L d molecules react consistently with all anti-H-2.28 sera which we have tested (Lemonnier et al 1975, Morello et al 1977, N6auport-Saut6s et al 1977a, b, 1978, D6mant et al 1978, McKenzie et al 1977. So far, they have not been found to react with any serum containing antibodies against the presently known specificities other than those of the H-2.28 family.…”

“…However, an alternative view has been taken by Hansen, Sachs and collaborators, who propose that the H-2L molecule is detectable by antibodies specific for H-2L products that are present in antisera against the public specificities, but not in antisera against the private specificities. According to this view, H-2L molecules do not bear the specificities of the H-2.28 family, but bear previously unknown specificities which are identifiable by means of an BALB/c-H-2 din2 anti-BALB/c serum (analogous to AS 506, McKenzie et al 1977) and for which the symbols H-2.64 and H-2.65 are proposed (Hansen and Sachs 1978).…”

Thymus and Lymphohemopoietic Cells: Their Role in T Cell Maturation in Selection of T Cells' H‐2‐Restriction‐Specificity and in H‐2 Linked Ir Gene Control

“…a) Complex Formation: The cause of dominant D'' low response to vaccinia seems to be that D'' -)-vaccinia do not form immunogenic complexes. This explanation would fit a single recognition site theory but might in rare cases also influence immunogenicity in a dual recognition concept (Blanden et al, 1977). Although no data presently support this notion, related experiments are in progress.…”

“…This speculation is apphcable as a general rule only to NAD-single receptor models (Doherty & Zinkemagel, 1975, Rosenthal et al, 1977, Schwartz, 1978, Benacerraf, 1978. However, it may also explain rare cases of low responses due to steric interference between R and X (see e. g. Blanden et al, 1977). This model attributes a receptor function to R on macrophages (K, I, D) or other cells (K, D) as most clearly formulated by Benacerraf (1978).…”

Cytotoxic T-cell responses show more restricted specificity for self than for non-self H-2D-coded antigens

“…The contribution of H-2K and H-2D regions has been clarified by the use of H-2 mutants. Biological and biochemical studies of a series of mutants in the H-2K region of the H-2 b haplotype have demonstrated first that the classical, serologically-defined H-2 alloantigen molecule bearing private specificities is essential for Tc cell recognition of infected-self cells (11)(12)(13)(14)(15), and second, that the specificity of self H-2K antigen recognition by Tc cells is exquisite (11)(12)(13)16). For example, mutant and wild-type H-2K molecules which are qualitatively indistinguishable by serological criteria (17,18) and which crossreact markedly when recognized by alloreactive Tc cells (19)(20)(21), do not crossreact when recognized by Tc cells specific for virus-plus-self (11)(12)(13)16).…”