Costimulation of T cells by OX40, 4-1BB, and CD27

Costimulatory signals have been defined as signals brought about by ligation of membrane bound molecules that synergize with, or modify, signals provided when the T cell receptor engages peptide-MHC complexes. In large part, costimulatory signals are essential for many facets of a T cell response, and the general rule is that without these signals, a T cell is ineffective and may often succumb to death or become unresponsive. Until recently, costimulation has been dominated by studies of the Ig superfamily member, CD28, a constitutively expressed molecule that is required to initiate a majority of T cell responses. However, growing evidence over the past few years has now shown that several members of the TNFR family, OX40 (CD134), 4-1BB (CD137), and CD27, are equally important to the effective generation of many types of T cell response. In contrast to CD28, these molecules are either induced or highly upregulated on the T cell surface a number of hours or days after recognition of antigen, and appear to provide signals to allow continued cell division initially regulated by CD28 and/or to prevent excessive cell death several days into the response. An argument can be made that these molecules control the absolute number of effector T cells that are generated at the peak of the immune response and dictate the frequency of memory T cells that subsequently develop. The exact relationship between OX40, 4-1BB, and CD27, is at present unknown, including whether these molecules act together, or sequentially, or control differing types of T cell response. This review will focus on recent studies of these molecules and discuss their implications.