CD45 (Cluster of Differentiation 45), also known as protein tyrosine phosphatase receptor type C (PTPRC), is a transmembrane protein tyrosine phosphatase critical for lymphocyte function. As a major phosphatase in immune cells, CD45 regulates signal transduction through the T-cell receptor (TCR) and B-cell receptor (BCR), making it essential for adaptive immunity. In the nervous system, CD45 is expressed on microglia and certain neurons, where it plays roles in neuroinflammation and neuronal signaling.
¶ Gene and Expression
The human PTPRC gene is located on chromosome 1q31-32 and encodes a protein of 1,268-2,047 amino acids depending on isoform. Multiple isoforms are generated through alternative splicing:
- Immune cells: T cells, B cells, NK cells, macrophages
- Brain: Microglia, some neurons, endothelial cells
- Isoform patterns: Different isoforms innaive vs. memory T cells
- Development: Regulated expression during hematopoiesis
CD45 has a complex multi-domain structure:
- Extracellular domain: Variable due to alternative splicing
- Single transmembrane domain: Connects to cytoplasmic portion
- Cytoplasmic domain: Contains two phosphatase domains (D1 and D2)
- Fibronectin type III repeats: Three repeats in extracellular region
- C-terminal regulatory tail: Controls phosphatase activity
CD45 is a master regulator of immune cell signaling:
- Dephosphorylation: Removes inhibitory phosphates from Src family kinases
- TCR signaling: Essential for T-cell activation
- BCR signaling: Regulates B-cell receptor signaling
- Cytokine signaling: Modulates responses to interleukins
- Cell survival: Prevents apoptosis in lymphocytes
CD45 has unique enzymatic properties:
- Active phosphatase domain: D1 domain has catalytic activity
- Dimerization: Regulates enzyme activity
- Substrate specificity: Multiple protein substrates
- Auto-dephosphorylation: Regulates its own function
CD45 in AD:
- Microglial activation: Regulates inflammatory responses
- Aβ clearance: Modulates microglial phagocytosis
- Neuroinflammation: Affects cytokine production
- Therapeutic target: CD45 modulators in development
- Genetic associations: PTPRC variants linked to AD risk
In PD:
- Microglial CD45: Regulates neuroinflammation in substantia nigra
- Dopaminergic neurons: May affect neuron survival
- T-cell infiltration: Associated with Lewy bodies
- Therapeutic potential: Modulating CD45 signaling
- Demyelination: T-cell CD45 in autoimmune attack
- Microglial function: Regulates CNS inflammation
- Therapeutic targeting: CD45 antibodies in trials
CD45 isoforms have distinct functions:
- CD45RA: Naive T cell isoform
- CD45RO: Memory T cell isoform
- CD45RB: B cells and some T cells
- CD45RC: Subset of T cells
- Isoform switching: Occurs during immune cell activation
- Immune activation: Marker of immune cell status
- Disease activity: Levels in neurodegeneration
- Therapeutic monitoring: Response to immunomodulation
- Monoclonal antibodies: In clinical trials for autoimmune disease
- Small molecule inhibitors: Under development
- Gene therapy: For immune disorders
- Flow cytometry: CD45 isoforms on immune cells
- Immunohistochemistry: Tissue localization
- Western blot: Isoform detection
- Knockout mice: Severe immunodeficiency
- Transgenic models: Isoform-specific studies
- Chimeric models: Human immune cell reconstitution