Abstract
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.
Highlights
Antigen-specific T cell activation is triggered by the T cell receptor (TCR) recognition of a cognate peptide presented by antigen presenting cells (APC), but it is overall controlled by a plethora of other cell surface receptors that either increase or repress the strength of the signals, the combination of which determines the outcome of T cell-mediated responses
Inhibitory co-receptors, such as the immune checkpoints Programmed cell death protein 1 (PD-1), Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), Lymphocyte-activation gene 3 (LAG-3), and B- and T-lymphocyte attenuator (BTLA) are crucial to halt the progression or to terminate cell activation once they become expressed, given that they are strongly induced upon activation [1,2,3,4,5]
It cannot be unexpected that T cell-expressed inhibitory receptors functionally and physically associate with kinases that are known to be crucial to T cell activation
Summary
Antigen-specific T cell activation is triggered by the T cell receptor (TCR) recognition of a cognate peptide presented by antigen presenting cells (APC), but it is overall controlled by a plethora of other cell surface receptors that either increase or repress the strength of the signals, the combination of which determines the outcome of T cell-mediated responses. The number and diversity of effectors that associate with CD5 and/or CD6, depending or not on tyrosine phosphorylation, would not give an obvious idea of the repressive potential of the receptors, given that many interacting partners are effectively protein tyrosine kinases that are normally associated with signaling progression These include LCK, FYN, ZAP70, and in the case of CD6, the TEC-family kinase ITK [32, 35,36,37]. Some of the papers that reported the phosphoprotein-dependent molecular interactions of CD6 described the coincident finding that the same molecules could dock onto the phosphotyrosine sites of Linker for activation of T cells (LAT), a membrane-bound adaptor of the main axis of the TCR-mediated pathway. A recent report has described the interaction of CD6 with the protein phosphatase SHP1 [26], constituting this the first solid biochemical evidence that CD6 can couple to inhibitory signaling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
