The first evidence of presence of a neutralizing substance in the blood that could counter infections came when Emil von Behring along with Kitasato Shibasaburō in 1890 developed effective serum against diphtheria. This they did by transferring serum produced from animals immunized against diphtheria to animals suffering from it. Transferring the serum thus could cure the infected animals. Behring was awarded the Nobel Prize for this work in 1901.
At this time though the chemical nature of what exactly in the blood conferred this protection was not known. In a few decades to follow, it was shown that the protective serum could neutralize and precipitate toxins, and clump bacteria. All these functions were attributed to different substances in the serum, and named accordingly as antitoxin, precipitin and agglutinin. That all the three substances were one entity (gamma globulins) was demonstrated by Elvin A. Kabat in 1939. In the preceding year Kabat had demonstrated the heterogeneity of antibodies through ultracentrifugation studies of horses' sera.
Until this time, cell-mediated immunity and humoral immunity were considered to be contending theories to explain effective immune response, but the former lagged behind owing to lack of advanced techniques. Cell-mediated immunity got an impetus in its recognition and study when in 1942, Merrill Chase successfully transferred immunity against tuberculosis between pigs by transferring white blood cells.
It was later shown in 1948 by Astrid Fagraeus in her doctoral thesis that the plasma B cells are specifically involved in antibody production. The role of lymphocytes in mediating both cell-mediated and humoral responses was demonstrated by James Gowans in 1959.
In order to account for the wide range of antigens the immune system can recognize, Paul Ehrlich in 1900 had hypothesized that preexisting "side chain receptors" bind a given pathogen, and that this interaction induces the cell exhibiting the receptor to multiply and produce more copies of the same receptor. This theory, called the selective theory was not proven for next five decades, and had been challenged by several instructional theories which were based on the notion that an antibody would assume its effective structure by folding around the antigen. In the late 1950s however, the works of three scientists—Jerne, Talmage and Burnet (who largely modified the theory)—gave rise to the clonal selection theory, which proved all the elements of Ehrlich's hypothesis except that the specific receptors that could neutralize the agent were soluble and not membrane-bound.
The clonal selection theory was proved correct when Sir Gustav Nossal showed that each B cell always produces only one antibody.
In 1974, the role of MHC in antigen presentation was demonstrated by Rolf Zinkernagel and Peter C. Doherty.