A patient with no prior transplants or transfusions receives a kidney. Within one week, T cells are found infiltrating the graft and attacking donor cells. T cells are binding directly to intact MHC molecules on the surface of transplanted cells without any antigen processing step. Which pathway describes this?
AIndirect allorecognition, where recipient APCs process donor proteins and present peptides on recipient MHC
BDirect allorecognition, where recipient T cells bind intact donor MHC molecules on transplanted cells
CHyperacute rejection, mediated by preformed antibodies against donor endothelium
DChronic rejection, driven by antibody-mediated vascular damage over months to years
Direct allorecognition is the dominant pathway in early acute rejection. Recipient T cells — trained to recognize peptide on self-MHC — bind directly to structurally foreign donor MHC molecules. This is unusual because T cells normally require both peptide and self-MHC, but donor MHC is different enough in structure that it activates T cells as if it were a peptide-loaded self-MHC complex. The absence of preformed antibodies rules out hyperacute rejection. Indirect allorecognition (where recipient APCs first process donor antigens) becomes more prominent later as donor cells die and shed proteins.
Question 2 Multiple Choice
Transplant rejection generates a more powerful T cell response than most viral infections. What is the primary reason for this unusual magnitude?
ADonor cells express higher levels of MHC than infected host cells, providing more signal per cell
BThe transplant introduces a large bolus of antigen simultaneously rather than gradually
CUp to 1-10% of recipient T cells can respond to a single foreign MHC type via direct allorecognition, compared to the tiny fraction that responds to any single conventional antigen
DImmunosuppressive drugs administered post-transplant paradoxically stimulate T cell responses
The magnitude of the alloreactive response is explained by cross-reactivity in direct allorecognition. A conventional foreign antigen activates only a small specific T cell clone — perhaps 1 in 100,000 cells. But donor MHC molecules, being structurally distinct from self-MHC, can be recognized by many T cell clones that were originally trained against various self-MHC-peptide combinations — up to 1-10% of the entire repertoire. This is a 1,000-fold or greater difference in scale and explains why rejection can occur even when only a few HLA antigens are mismatched.
Question 3 True / False
Direct allorecognition is immunologically unusual because it involves recipient T cells responding to intact, unprocessed MHC molecules on donor cells rather than the normal pattern of recognizing peptide-MHC complexes.
TTrue
FFalse
Answer: True
Under normal circumstances, T cells require two signals: a peptide fragment and self-MHC presenting it. In direct allorecognition, the donor MHC molecule itself functions as the stimulus, activating recipient T cells without any antigen processing step. This works because donor MHC molecules are structurally different enough from self-MHC that they effectively 'look like' the peptide-plus-self-MHC signal the T cell was trained to detect. The structural foreignness of the whole MHC molecule triggers the response, bypassing the normal requirement for peptide presentation.
Question 4 True / False
Immunosuppressive drugs used to prevent transplant rejection can be targeted specifically to suppress primarily anti-donor T cell responses, leaving most other immune functions intact.
TTrue
FFalse
Answer: False
Current immunosuppressive agents — calcineurin inhibitors, mycophenolate, corticosteroids — broadly suppress T cell activation and lymphocyte proliferation regardless of the antigen target. They cannot distinguish anti-donor T cells from T cells responding to a bacterial infection or a malignant cell. This is the fundamental dilemma of transplant medicine: the same surveillance mechanisms that reject the graft also protect against pathogens and tumors. Patients on long-term immunosuppression face elevated risks of opportunistic infections and certain malignancies. Inducing graft-specific tolerance — using regulatory T cells or other targeted mechanisms — remains an active research frontier precisely because it promises to escape this tradeoff.
Question 5 Short Answer
Explain why MHC polymorphism — the extreme genetic diversity in HLA genes that evolved as a population-level defense against pathogens — becomes the central obstacle in organ transplantation.
Think about your answer, then reveal below.
Model answer: MHC diversity evolved because no single MHC variant can present all possible pathogen-derived peptides; populations with diverse HLA alleles collectively resist a wider range of pathogens. This evolutionary benefit becomes a transplantation obstacle because HLA genes are the most polymorphic in the human genome: any two unrelated individuals almost certainly carry different HLA alleles. When an organ is transplanted, the recipient's T cells encounter donor MHC as structurally foreign and mount an attack. The more HLA mismatches between donor and recipient, the more T cell clones are activated and the more intense the rejection. The very polymorphism that provides population-level resilience against pathogens guarantees that donor organs will appear foreign to the recipient immune system.
This evolutionary logic explains why perfect immunological matching between unrelated donors is essentially impossible — the more diverse the population's MHC repertoire, the harder it is to find a donor whose HLA the recipient's immune system won't attack. Living related donors (who share more HLA alleles) produce better transplant outcomes for this reason. The challenge of transplant medicine is thus not a design flaw but a consequence of how immune self/non-self recognition evolved at the population level.