SunlmaryPeptides from donor major histocompatibility complex (MHC) molecules were examined for their activation of allogeneically primed T cells. After immunization with either allogeneic spleen cells or a skin allograft, primed T cells proliferate in response to peptides derived from polymorphic regions of a and B chains of dass II allo-MHC molecules. The results demonstrate that presentation of donor-MHC peptides by host-derived antigen-presenting cells is a common event in vivo. Thus, self-restricted T cell recognition of processed alloantigens may play a critical role in transplantation. An in-depth understanding of this response may result in the development of additional molecular therapies to combat allograft rejection. During transplantation or aUograft rejection, determinants encoded within the MHC of the donor are recognized by T lymphocytes of the recipient. This recognition results in a potent immunological reaction in which donor cells are rapidly and specifically killed, and the graft is destroyed (1, 2). It is generally accepted that T cells recognize foreign antigens in the form of peptides presented in association with self-MHC molecules. However, the molecular basis for the recognition of the allogeneic target is still controversial. Three nonexclusive models for the target structure that is recognized by alloreactive T lymphocytes have been proposed: (a) alloreactive T cells recognize polymorphic motifs present on the intact allo-MHC molecule, regardless of peptides bound to them; (b) self-(recipient) or allo-(donor) derived peptides interact with the native aUo-MHC molecules to create a series of new determinants recognized by T cells; (c) the allo-MHC molecules are processed into peptides and presented by self-MHC molecules to specific T cells (3, 4). In this report, we provide evidence for the third alternative. Materials and MethodsPeptides. Peptides were synthesized in the Norris Cancer Center Microchemistry Laboratory (USC) with an automated peptide synthesizer (430A; Applied Biosystems Inc., Foster City, CA) using modified Merrifield chemistry. These peptides were also used in the studies reported in reference 5.T Cell Proliferation. B10.A (H-2'), BALB/c (H-2d), and SJL/J (H-2') mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and bred at UCLA. BALB/c and SJL/J mice were immunized in the foot pads with 2 x 107 irradiated sphnocytes in 25/~1, along with 25 #1 of CFA (Difco Laboratories, Detroit, MI) on the dorsal surface of the foot. Popliteal lymph node cells and splenocytes were obtained 10 d later, and used in antigen-induced proliferation assays. Cell suspensions were cultured in 0.2 ml of serum-flee HL-1 medium (Ventrex, Portland, ME), containing 2 mM glutamine in 96-weU plates for 4 d (5 x 10 s cells/well). Proliferation was assessed by the incorporation of I/~Ci [3H]thymidine during the last 18 h of culture.Skin Grafts. SJL/J and BALB/c mice were anesthetized, and then engrafted on the left side of the back with back skin (1-cm disk) from B10.A mice, according to th...

DNA-mediated gene transfer was used to identify cloned class I genes from the major histocompatibility complex of the BALB/c mouse. Three genes encoding the transplantation antigens H-2 Kd, Dd and Ld were identified as well as genes encoding the Qa-2,3 and two TL differentiation antigens. As many as 10 putative novel class I genes were detected by the association of their gene products with beta 2-microglobulin. Alloantiserum prepared to one of the novel antigens was used to demonstrate the expression of the previously undetected antigen on spleen cells of various inbred, congeneic, and recombinant congeneic strains of mice.

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Cancers induced by physical or chemical carcinogens express tumor-specific antigens that are uniquely specific for any given tumor; therefore, there is a seemingly endless variety of these unique antigens. We have studied a UV-induced fibrosarcoma, designated 1591, to elucidate the obscure molecular nature and genetic origins of unique tumorspecific antigens. A monoclonal antibody raised against syngeneic 1591 tumor cells has unique tumor specificity. This tumor-specific monoclonal antibody precipitated from the tumor a 45-kDa molecule associated with a 12-kDa molecule having the pI of 82-microglobulin. This and other evidence indicated that the 1591 tumor expresses a novel class I molelule. A 1591 variant selected for the absence of binding to the monoclonal antibody lacked the novel class I MHC molecule as well as reactivity with cytotoxic T

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