Cell Activation & Gene Expression
ABOUT
Triggering of the T cell receptor (TCR) initiates a signaling cascade resulting in the activation of the T cell. TCR-mediated biochemical signals are integrated alongside those resulting from the stimulation of other receptors whose function is to modulate the overall response. CD5 and CD6 are receptors expressed at the surface of T lymphocytes that have key roles in regulating T cell signaling. They are members of the scavenger receptor cysteine-rich (SRCR) superfamily of proteins, and during antigen presentation both molecules localize at the immunological synapse, interact with the TCR signaling machinery and help fine-tuning the activation signals. As CD5 and CD6 do not have enzymatic activity, their function is determined by molecular associations established with intracellular signaling effectors. Performing wide range screens, we are determining the signaling/structural mediators that define the receptors’ role, both in the regulation of signal transduction as well as in contributing to the architecture of the immunological synapse. We have extended our search for function to other members of the SRCR family. Through a systematic production of the extracellular domain of the receptors and detecting binding to a variety of cell targets, our aim is to discover the ligands of SRCR molecules and to determine their roles upon ligand binding.
RESEARCH
We have recently proposed that CD6 is a negative regulator of TCR-mediated signaling. This represents a paradigm shift and may have implications on strategies for regulating CD6-dependent functions. The CD6 gene has very recently been established as a multiple sclerosis susceptibility gene, and immunotherapy using CD6 antibodies is being currently used in other inflammatory disorders such as psoriasis, rheumatoid arthritis or Sjörgren’s syndrome. On the other hand, CD5 has long been known to functionally work as a signaling inhibitor, recruiting to the sites of antigen recognition the tyrosine phosphatase SHP-1, which dampens ongoing phosphorylation reactions. We have recently proposed an alternative mode of CD5 inhibitory signaling: stimulation of CD5 results in the tyrosine phosphorylation of the kinase Fyn at its C-terminal inhibitory tyrosine residue, thus inactivating the kinase. These inhibitory actions of CD5 are further amplified by an increased expression of CD5 upon T cell receptor triggering.

Team
Selected Publications
The CD6 interactome orchestrates ligand-independent T cell inhibitory signaling. Cell communication and signaling : CCS22(1):, 2024. [Journal: Article] [IF: 8.2 (*)]
DOI: 10.1186/s12964-024-01658-y SCOPUS: 85194218997
Oliveira L., Silva M.C., Gomes A.P., Santos R.F., Cardoso M.S., Nóvoa A., Luche H., Cavadas B., Amorim I., Gärtner F., Malissen B., Mallo M., Carmo A.M.
CD5L as a promising biological therapeutic for treating sepsis. Nature Communications15(1):, 2024. [Journal: Article] [CI: 3] [IF: 14.7 (*)]
DOI: 10.1038/s41467-024-48360-8 SCOPUS: 85193351776
Pereira J.L., Arede L., Ferreira F., Matos A., Pereira D., Santos R.F., Carmo A.M., Oliveira M.J., Machado J.C., Duarte D., dos Santos N.R.
Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma. Leukemia:, 2024. [Journal: Article] [IF: 12.8 (*)]
DOI: 10.1038/s41375-024-02446-w SCOPUS: 85207331538
Henriques S.N., Oliveira L., Santos R.F., Carmo A.M.
CD6-mediated inhibition of T cell activation via modulation of Ras. Cell communication and signaling : CCS20(1):, 2022. [Journal: Article] [CI: 4] [IF: 8,4]
DOI: 10.1186/s12964-022-00998-x SCOPUS: 85142255413
Cardoso M.S., Santos R.F., Almeida S., Sá M., Pérez-Cabezas B., Oliveira L., Tavares J., Carmo A.M.
Physical Interactions With Bacteria and Protozoan Parasites Establish the Scavenger Receptor SSC4D as a Broad-Spectrum Pattern Recognition Receptor. Frontiers in Immunology12:, 2021. [Journal: Article] [CI: 7] [IF: 8,8]
DOI: 10.3389/fimmu.2021.760770 SCOPUS: 85122481820
Pinto C., Sousa D., Ghilas V., Dardis A., Scarpa M., Macedo M.F.
Acid sphingomyelinase deficiency: A clinical and immunological perspective. International Journal of Molecular Sciences22(23):, 2021. [Journal: Review] [CI: 24] [IF: 6,2]
DOI: 10.3390/ijms222312870 SCOPUS: 85119904729
Melum E., Jiang X., Baker K.D., Macedo M.F., Fritsch J., Dowds C.M., Wang J., Pharo A., Kaser A., Tan C., Pereira C.S., Kelly S.L., Duan J., Karlsen T.H., Exley M.A., Schütze S., Zajonc D.M., Merrill A.H., Schuchman E.H., Zeissig S., Blumberg R.S.
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin. Nature Immunology20(12):1644-1655, 2019. [Journal: Article] [CI: 42] [IF: 20,5]
DOI: 10.1038/s41590-019-0504-0 SCOPUS: 85074348323
Gonçalves C., Henriques S., Santos R., Carmo A.
CD6, a rheostat-type signalosome that tunes T cell activation. Frontiers in Immunology9:, 2018. [Journal: Review] [CI: 31] [IF: 4,7]
DOI: 10.3389/fimmu.2018.02994 SCOPUS: 85059925855
Nogueira E., Lager F., Le Roux D., Nogueira P., Freitas J., Charvet C., Renault G., Loureiro A., Almeida C.R., Ohradanova-Repic A., Machacek C., Bernardes G.J.L., Moreira A., Stockinger H., Burnet M., Carmo A.M., Gomes A.C., Preto A., Bismuth G., Cavaco-Paulo A.
Enhancing methotrexate tolerance with folate tagged liposomes in arthritic mice. Journal of Biomedical Nanotechnology11(12):2243-2252, 2015. [Journal: Article] [CI: 55] [IF: 3,9]
DOI: 10.1166/jbn.2015.2170 SCOPUS: 84941551653
Oliveira M.I., Gonçalves C.M., Pinto M., Fabre S., Santos A.M., Lee S.F., Castro M.A.A., Nunes R.J., Barbosa R.R., Parnes J.R., Yu C., Davis S.J., Moreira A., Bismuth G., Carmo A.M.
CD6 attenuates early and late signaling events, setting thresholds for T-cell activation. European Journal of Immunology42(1):195-205, 2012. [Journal: Article] [CI: 61] [IF: 5]
DOI: 10.1002/eji.201040528 SCOPUS: 84855225261