A tumor cell downregulates MHC class I expression to evade immune surveillance. Which killing mechanism would be most impaired by this strategy?
AADCC by NK cells, because NK cells require MHC class I presentation to identify the target
BCytotoxic T lymphocyte (CTL) killing, because CTLs recognize antigen presented on MHC class I via their T cell receptors
CADCC would be unaffected, but complement-dependent cytotoxicity would be eliminated
DBoth CTL killing and ADCC equally, since both pathways converge on the same MHC-restricted recognition step
Cytotoxic T lymphocytes (CTLs) are MHC class I-restricted: they can only recognize and kill a target if the target presents antigen on MHC class I molecules. Downregulating MHC class I is a direct evasion of CTL killing. ADCC, by contrast, does not require MHC recognition at all — the antibody provides specificity by binding surface antigens, and NK cells detect the Fc regions of the bound antibodies through FcγRIIIa (CD16). As long as the tumor expresses the surface antigen targeted by the antibody, ADCC can still proceed even with no MHC class I present.
Question 2 Multiple Choice
Which part of an antibody molecule triggers ADCC, and which cell receptor on the effector cell does it engage?
AThe Fab region binds to FcγRIIIa (CD16) on NK cells, crosslinking the receptor to activate killing
BThe Fc region of surface-bound antibody is recognized by FcγRIIIa (CD16) on NK cells, triggering degranulation
CThe variable regions of the antibody bind directly to activating receptors on NK cells, bypassing the Fc region entirely
DThe Fc region binds to MHC class I on the NK cell, which provides the activation signal for cytotoxicity
In ADCC, the Fab regions are occupied binding antigen on the target cell surface. The Fc regions project outward and are recognized by FcγRIIIa (CD16) on NK cells (and to a lesser extent macrophages and eosinophils). Crosslinking of multiple FcγRIIIa receptors by clustered Fc regions triggers ITAM-mediated intracellular signaling, leading to degranulation of perforin and granzymes toward the target. The specificity comes entirely from the antibody's Fab-antigen interaction; the NK cell's FcγRIIIa is the activating receptor, not an antigen-recognition receptor.
Question 3 True / False
ADCC is triggered when NK cells directly recognize antigens on target cells through their own antigen-specific receptors.
TTrue
FFalse
Answer: False
NK cells do not have antigen-specific receptors like T cell receptors. In ADCC, the specificity for the target cell comes entirely from the antibody — its Fab regions bind to surface antigens. The NK cell detects not the antigen but the Fc region of the antibody that has already bound the target. It is the antibody coating the target cell that signals 'destroy this cell,' and the NK cell simply responds to that coating via FcγRIIIa. This is precisely what makes ADCC a bridge between adaptive (antibody) and innate (NK cell) immunity.
Question 4 True / False
Removing the core fucose residue from the Fc region of a therapeutic antibody enhances its ability to trigger ADCC.
TTrue
FFalse
Answer: True
The N-linked glycan at Asn-297 in the Fc region of IgG influences how tightly the Fc binds to FcγRIIIa. Afucosylation (removal of the core fucose) dramatically increases the affinity of Fc for FcγRIIIa, leading to stronger receptor crosslinking, more robust activating signals in NK cells, and enhanced ADCC activity. This is why next-generation therapeutic monoclonal antibodies (e.g., obinutuzumab vs. rituximab) are often engineered with afucosylated Fc regions to improve clinical efficacy through enhanced ADCC.
Question 5 Short Answer
Why is ADCC effective against target cells that have downregulated MHC class I expression, a strategy commonly used by viruses and tumors to evade cytotoxic T cells?
Think about your answer, then reveal below.
Model answer: ADCC does not use MHC-restricted recognition at any step. The antibody's Fab regions bind directly to antigens expressed on the target cell surface (viral proteins, tumor-associated antigens), and the NK cell's FcγRIIIa detects the Fc regions of the coating antibodies. Neither the antibody-antigen interaction nor the Fc-FcγR interaction requires MHC class I. As long as the target cell continues to express the antigen targeted by the antibody, it can be killed by ADCC regardless of its MHC class I status. This makes ADCC an important immunological backup against pathogens and tumors that exploit MHC downregulation to hide from T cells.
This complementarity — CTLs killing MHC-expressing targets, NK cells killing MHC-low targets (through missing-self recognition), and ADCC killing antibody-coated targets regardless of MHC — illustrates how the immune system uses overlapping and complementary mechanisms to prevent any single evasion strategy from being fully effective. Therapeutic antibodies exploit ADCC precisely because tumor cells frequently downregulate MHC; the antibody repaints the target in a way that NK cells can read without needing MHC-mediated antigen presentation.