The activation of complement proteins is an ancient form of soluble innate recognition and immunological defense against foreign invaders. In Immunity, Kolev et al. describe a role for the recognition of complement by CD4+ T helper type 1 (TH1) cells. Human CD4+ T cells express the complement regulator CD46, which recognizes the complement component C3b and can transmit signals via its cytoplasmic Cyt1 domain. Stimulation via the T cell antigen receptor (TCR) triggers expression of C3, which undergoes proteolytic cleavage to produce C3b and provide an autocrine stimulus for CD46 in TH1 cells. Stimulation via the TCR plus CD46 in vitro leads to increased metabolic responses, including upregulation of both glycolysis and oxidative phosphorylation, increased activation of the metabolic checkpoint kinase mTORC1 and increased expression of interferon-γ and IL-10. It remains unclear whether such responses require prior stimulation to generate memory T cells or whether signaling via costimulatory molecules, such as via CD28 or CTLA-4, interfere with CD46-dependent signaling pathways. Mechanistic details of these signaling cascades await future studies.

Immunity 42, 1033–1047 (2015)