Protein 4.1R negatively regulates CD8⁺ T‐cell activation by modulating phosphorylation of linker for activation of T cells

Abstract

Protein 4.1R, an 80 000 MW membrane skeleton protein, is a vital component of the red blood cell membrane cytoskeleton that stabilizes the spectrin-actin network and regulates membrane properties of deformability and mechanical stability. It has been shown that 4.1R is expressed in T cells, including CD8 + T cells, but its role in CD8 + T cells remains unclear. Here, we have explored the role of 4.1R in CD8 + T cells using 4.1R À/À mice. Our results showed that cell activation, proliferation and secretion levels of interleukin-2 and interferon-c were significantly increased in 4.1R À/À CD8 + T cells. Furthermore, the phosphorylation levels of linker for activation of T cells (LAT) and its downstream signaling molecule extracellular signal-regulated kinase were enhanced in the absence of 4.1R. In vitro co-immunoprecipitation experiments showed a direct interaction between 4.1R and LAT. Moreover, 4.1R À/À CD8 + T cells and mice exhibited an enhanced T-cell-dependent immune response. These data enabled the identification of a negative regulation function for 4.1R in CD8 + T cells by a direct association between 4.1R and LAT, possibly through inhibiting phosphorylation of LAT and then modulating intracellular signal transduction.

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study

“…Erythrocyte membrane protein band 4.1 (EPB41) links cell membrane proteins to the cytoskeleton and is involved in many cellular processes such as cell proliferation, cytokine secretion, cell adhesion, and cell migration [ 29 , 30 , 31 , 32 , 33 , 34 ]. EPB41 suppresses epidermal growth factor receptor (EGFR) activation [ 29 ] and thus plays an important role as a tumor suppressor in cancer development.…”

“…Rare variants significantly associated with KC across several association test methods are shown in Table 3 and Figure 2. Several of the genes described here can be assigned to categories that are involved in the development of solid tumors: MC1R is involved in pigmentation/UV protection [27,28], EPB41 [29][30][31][32][33][34] and MYCT [35][36][37][38] in tumor suppression, and ADGRG3 in immunomodulation [39][40][41][42]. Studies on MGME1 suggest a direct involvement in cancer development and progression [43,44], and finally upregulation of the EPH8A gene expression was associated with a poor prognosis in ovarian, oral tongue, and gastric cancers [45][46][47].…”

Cytoskeletal Protein 4.1R in Health and Diseases

“…Additional investigations have demonstrated that 4.1R suppresses the activation of CD4 + T cells, thereby mitigating pathogenic autoimmunity in the progression of multiple sclerosis and experimental autoimmune encephalomyelitis progression [48]. Recent research has also indicated that 4.1R is a negative regulator of TCR signaling in CD8 T cells through its direct association with LAT [29]. In mast cells, Draberova et al indicated that 4.1R acts as a positive regulator in the initial activation events following FcεRI triggering through its direct interaction with both LAT1 and LAT2 [27].…”

Cytoskeletal Protein 4.1R Is a Positive Regulator of the FcεRI Signaling and Chemotaxis in Mast Cells

“…Further experiments showed that protein 4.1R could suppress activation of CD4 + T cells and thereby prevent progression of pathogenic autoimmunity (36). Recently published data concluded that the 4.1R protein is also a negative regulator of TCR signaling in CD8 + cells (37). However, the role of the 4.1R protein in the function of other immunoreceptors is not understood.…”