Isherwood was born in 1906 in Disley, Cheshire, the son of an army officer, who was killed in World War I. In his childhood Isherwood travelled around with his father's regiment. In 1914 he was sent to St. Edmund's preparatory school, where he made friends with W.H. Auden, later his lover. Isherwood studied at Cambridge, without taking a degree. After Cambridge he worked as a private tutor, and from 1930 to 1933 he taught English in Germany. The experiences provided him with the material for his most famous books, The Berlin Stories - two tales of the city, Mr Norris Changes Trains, and Goodbye to Berlin, which inspired the musical Cabaret. In 1938 Isherwood and Auden went to China, and Isherwood wrote Journey To A War. With Auden he emigrated to the US, becoming an American citizen in 1946.

Isherwood settled in 1939 in southern California, where he worked as a teacher and worked on Hollywood scripts. During 1941-42, he worked at a Quaker hostel in Pennsylvania with refugees from Europe. In 1943 he became a follower of Swami Prabhavananda, producing several works on Indian Vedanta in the following decades, and several more novels. In 1975, he won the Brandeis Medal for Fiction. His novels increasingly referred openly to his homosexuality, and he became a leading spokesman for gay rights. He died in Santa Monica, on January 4, 1986.

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