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The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3\u03b3\u03b5, CD3\u03b4\u03b5, and CD3\u03b6\u03b6) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C\/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3\u03b6, ZAP70, and PLC\u03b31 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C\/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C\/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.\n                  <\/jats:p>","DOI":"10.7554\/elife.88225","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T09:38:02Z","timestamp":1695893882000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88225","source":"Crossref","is-referenced-by-count":0,"title":["The CD4 transmembrane GGXXG and juxtamembrane (C\/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-LCK interactions"],"prefix":"10.7554","volume":"12","author":[{"given":"Mark S","family":"Lee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03m2x1q45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunobiology, The University of Arizona College of Medicine","place":["Tucson, United 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