Provided herein are methods and compositions for the removal and isolation of target blood cells from a whole blood sample using bifunctional fusion proteins. The fusion proteins may include a first binding domain that is specific for a red blood cell (RBC) surface antigen, a cleavable or stable linker, and a second binding domain that is specific for a cell-surface expressed antigen of a target blood cell. The methods may involve adding the fusion protein to the whole blood, followed by centrifugation to produce a pellet comprising RBCs bound to target blood cells. The target blood cells may include non-RBC cell types such as antigen-presenting cells, which may express an MHC-presented peptide derived from an infectious agent or cancer-associated antigen. The target blood cells may be further separated from RBCs by lysing or cleaving the linker. Also provided are compositions, kits, and methods for identifying infected or cancerous white blood cells using MHC-targeted binding domains.