Tyrosine phosphorylation is a common means of regulating protein functions and signal transduction in multiple cells. Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes that remove phosphate groups from tyrosine residues of target proteins and change their functions. Among them, receptor-type PTPs (RPTPs) exhibit a distinct spatial pattern of expression and play essential roles in regulating neurite outgrowth, axon guidance, and synaptic organization in developmental nervous system. Some RPTPs function as essential receptors for chondroitin sulfate proteoglycans that inhibit axon regeneration following CNS injury. Interestingly, certain RPTPs are also important to regulate functions of immune cells and development of autoimmune diseases. PTPσ, a RPTP in the LAR subfamily, is expressed in various immune cells and regulates their differentiation, production of various cytokines and immune responses. In this review, we highlight the physiological and pathological significance of PTPσ and related molecules in both nervous and immune systems.