CD4 and autoimmune disease: In autoimmune diseases, a complex interplay of factors, including prolonged antigenic stimulation, restricted CD4+ T-cell responses, limited co-stimulation during initial T-cell activation, diminished gamma-chain cytokine signaling, and characteristics of the tissue microenvironment (e.g., hypoxia, nutrient deficiencies, pH abnormalities), contributes to T-cell differentiation along exhaustion pathways (16).