The partitioning of membrane-associated proteins into discrete microdomains (commonly dubbed “membrane rafts”) can profoundly influence their biological activities. Anderson et al.1 have shown that major histocompatibility complex (MHC) class II proteins are constitutively associated with membrane rafts in both mouse and human B cell lines. This association augments antigen presentation, particularly at lower experimental concentrations of antigen. Their proposed mechanism is that multiple antigen–class II complexes that are confined within individual membrane rafts become locally concentrated and thereby stimulate T cell receptors (TCRs) more efficiently. If this were so, it would be necessary for the number of antigen–class II complexes to exceed the number of membrane rafts on the antigen-presenting cell (APC) surface by several-fold. If complexes numerically exceeded rafts by n-fold, on average, each raft would have n complexes. As n falls below unity, the tendency for complexes to aggregate by virtue of their random association with rafts will fall to zero. Based on physical measurements, it can be estimated that the plasma membrane of a cell typically contains several thousand membrane rafts2,3. However, T cells can become activated by APCs that bear as few as 200 antigen–class II complexes on their surfaces1. Thus, under physiological conditions, n may often be less than 1. The mechanism of raft-enhanced antigen presentation proposed by Anderson et al. may be, therefore, of limited physiological relevance.
We suggest that at very low concentrations of antigen, the aggregation of class II with membrane rafts can usefully serve to increase the local concentration of antigen–class II complexes only if class II bearing specific antigen is preferentially recruited to a restricted pool of membrane rafts. Such recruitment could be initiated by the binding of cognate TCRs, leading to the preferential partitioning of specific antigen–class II complexes into membrane rafts located within the immunological synapse on the surface of the APC. In the THP-1 cell line, cross-linking antibodies to class II can induce it to enter membrane rafts, from which it is normally excluded in these cells4. Class II bearing specific antigen may be similarly induced to enter the membrane rafts of B cells during interactions with T cells, though the constitutive presence of class II within the rafts makes this more difficult to observe1 (and R. Huby et al., unpublished data).
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