CD6, a rheostat-type signalosome that tunes T cell activation

Following T cell receptor triggering, T cell activation is initiated and amplified by the assembly at the TCR/CD3 macrocomplex of a multitude of stimulatory enzymes that activate several signaling cascades. The potency of signaling is, however, modulated by various inhibitory components already at the onset of activation, long before co-inhibitory immune checkpoints are expressed to help terminating the response. CD5 and CD6 are surface glycoproteins of T cells that have determinant roles in thymocyte development, T cell activation and immune responses. They belong to the superfamily of scavenger receptor cysteine-rich (SRCR) glycoproteins but whereas the inhibitory role of CD5 has been established for long, there is still controversy on whether CD6 may have similar or antagonistic functions on T cell signaling. Analysis of the structure and molecular associations of CD5 and CD6 indicates that these molecules assemble at the cytoplasmic tail a considerable number of signaling effectors that can putatively transduce diverse types of intracellular signals. Biochemical studies have concluded that both receptors can antagonize the flow of TCR-mediated signaling; however, the impact that CD5 and CD6 have on T cell development and T cell-mediated immune responses may be different. Here we analyze the signaling function of CD6, the common and also the different properties it exhibits comparing with CD5, and interpret the functional effects displayed by CD6 in recent animal models.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-032296 (PTDC/MED-IMU/32296/2017). Additional funds, including funding for CMG, were from the project Norte-01-0145-FEDER-000012-Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). SNH and RFS are recipients of Ph.D. studentships from FCT, references SFRH/BD/133312/2017 and SFRH/BD/110691/2015, respectively