Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection.

Abstract

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...

Coronary Arteries from Human Cardiac Allografts with Chronic Rejection Contain Oligoclonal T Cells: Persistence of Identical Clonally Expanded TCR Transcripts from the Early Post-Transplantation Period (Endomyocardial Biopsies) to Chronic Rejection (Coronary Arteries)

“…The direct recognition pathway involves recognition of allogeneic MHC/peptide complexes expressed on dendritic cells (passenger leukocytes) of the donor by T cells of the recipient. MHC molecules of the donor may directly present peptides to the T cells of the recipient (31). It has been proposed that molecular mimicry is the basis of this recognition (29,52).…”

“…However, stimulation of T cells of the recipient by donor APCs that may lack costimulatory molecules will lead to anergy, reducing the significance of this response after the early post-transplantation period (60 -64). The indirect recognition pathway involves presentation by APC of the recipient to T cells of the recipient of epitopes comprised of MHC molecules of the recipient and antigenic peptides derived from MHC Ags of the donor (27)(28)(29)(30)(31)(32)(33)(34)(35). The later should be available in high quantities in the graft, because of cell destruction at the site of the graft and possible shedding of MHC molecules.…”

“…DeBruyne et al (59) reported restricted V␤-gene segment use by bronchoalveolar lavage-derived T cell lines from patients with human lung allografts before and during rejection episodes. Two different mechanisms of Ag presentation, the direct and the indirect, are responsible for the recognition of organ drafts by T cells of the recipient (27)(28)(29)(30)(31)(32)(33)(34)(35). The direct recognition pathway involves recognition of allogeneic MHC/peptide complexes expressed on dendritic cells (passenger leukocytes) of the donor by T cells of the recipient.…”

“…Both are members of the Ig supergene family (26). T cells of the recipient recognize organ grafts by two different pathways of Ag presentation, the direct and the indirect (27)(28)(29)(30)(31)(32)(33)(34)(35). Antigenic specificity for the TCR is primarily associated with the sequences of the hypervariable, or CDR3, part of the ␤-chain TCR transcript (36 -39).…”

Inability to Induce Tolerance Through Direct Antigen Presentation

“…These studies, along with others using MHC class I (CI)-and class II (CII)-deficient donors (11), suggested that indirect antigen presentation is an important pathway mediating MHC CI-and MHC CII-disparate allograft rejection. Additionally, experiments using donor-derived peptides to stimulate alloreactive T cells and donor tissues derived from MHC-deficient mice confirmed indirect antigen presentation as an important mechanism in the rejection of allogeneic organs and tissues (4,5,9,(12)(13)(14)(15)(16)(17)(18). However, the lack of an in vivo model system restricted to recognizing directly presented donor alloantigen has made it difficult to ascertain the unique role of direct antigen presentation in allograft rejection.…”