Nutrients play a critical role in T cell immunity as a fourth signal (Signal 4), working alongside the established signals of antigen (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Nutrients such as glucose, amino acids, and lipids regulate T cell activation, differentiation, and function by interacting with these signals. This review summarizes the functional importance of Signal 4, the mechanisms of nutrient transport, sensing, and signaling, and their roles in T cell fate decisions and functional specialization. It also discusses how targeting nutrients can improve disease therapy. T cell activation requires nutrient uptake and metabolism, which are regulated by signals 1-3. Nutrients influence T cell differentiation into subsets like Th1, Th2, Th17, and Treg, and their functional specialization in different disease contexts. Nutrient availability affects T cell quiescence exit and activation, with glucose and amino acids playing key roles. The uptake of glucose and amino acids is regulated by transporters like GLUT1 and system L amino acid transporters, which are upregulated by signals 1 and 2. Nutrient sensing involves proteins that detect intracellular levels of amino acids, sugars, or lipids, leading to downstream signaling events that regulate mTORC1 activity and metabolic reprogramming. Amino acid sensing occurs at the lysosome and involves proteins like Sestrins, CASTOR1, and SAMTOR, which regulate mTORC1 signaling. Glucose and amino acids are interdependent in T cell activation, with glucose uptake promoting mTORC1 activity and amino acid transporters facilitating glucose uptake and glycolysis. Fatty acids and cholesterol also contribute to T cell activation, proliferation, and survival, with fatty acid uptake regulated by transporters and cholesterol affecting TCR signaling and immunological synapse formation. Nutrients shape T cell differentiation and function by influencing metabolic pathways and signaling events. Glucose metabolism is crucial for Th1, Th17, and Treg cell differentiation, with glycolysis promoting Th1 and Th17 cell generation and inhibiting Treg cell function. Amino acids like arginine and leucine influence T cell differentiation, with arginine promoting Th17 cell differentiation and leucine affecting Th1 and Th17 cell differentiation. Fatty acids and SCFAs (short-chain fatty acids) also impact T cell responses, with SCFAs promoting Treg cell differentiation and IL-22 production, while LCFAs enhance CD8+ T cell function and antitumor immunity. Nutrients also influence memory T cell development and function, with memory T cells relying on different metabolic pathways and nutrients depending on their tissue location. The interplay between nutrients and cytokine signaling (Signal 3) is crucial for coordinating nutrient uptake and metabolic rewiring with T cell fate. Overall, understanding how nutrients regulate T cell immunity in different microenvironments provides insights into adaptive immunity and therapeutic interventions.Nutrients play a critical role in T cell immunity as a fourth signal (Signal 4), working alongside the established signals of antigen (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Nutrients such as glucose, amino acids, and lipids regulate T cell activation, differentiation, and function by interacting with these signals. This review summarizes the functional importance of Signal 4, the mechanisms of nutrient transport, sensing, and signaling, and their roles in T cell fate decisions and functional specialization. It also discusses how targeting nutrients can improve disease therapy. T cell activation requires nutrient uptake and metabolism, which are regulated by signals 1-3. Nutrients influence T cell differentiation into subsets like Th1, Th2, Th17, and Treg, and their functional specialization in different disease contexts. Nutrient availability affects T cell quiescence exit and activation, with glucose and amino acids playing key roles. The uptake of glucose and amino acids is regulated by transporters like GLUT1 and system L amino acid transporters, which are upregulated by signals 1 and 2. Nutrient sensing involves proteins that detect intracellular levels of amino acids, sugars, or lipids, leading to downstream signaling events that regulate mTORC1 activity and metabolic reprogramming. Amino acid sensing occurs at the lysosome and involves proteins like Sestrins, CASTOR1, and SAMTOR, which regulate mTORC1 signaling. Glucose and amino acids are interdependent in T cell activation, with glucose uptake promoting mTORC1 activity and amino acid transporters facilitating glucose uptake and glycolysis. Fatty acids and cholesterol also contribute to T cell activation, proliferation, and survival, with fatty acid uptake regulated by transporters and cholesterol affecting TCR signaling and immunological synapse formation. Nutrients shape T cell differentiation and function by influencing metabolic pathways and signaling events. Glucose metabolism is crucial for Th1, Th17, and Treg cell differentiation, with glycolysis promoting Th1 and Th17 cell generation and inhibiting Treg cell function. Amino acids like arginine and leucine influence T cell differentiation, with arginine promoting Th17 cell differentiation and leucine affecting Th1 and Th17 cell differentiation. Fatty acids and SCFAs (short-chain fatty acids) also impact T cell responses, with SCFAs promoting Treg cell differentiation and IL-22 production, while LCFAs enhance CD8+ T cell function and antitumor immunity. Nutrients also influence memory T cell development and function, with memory T cells relying on different metabolic pathways and nutrients depending on their tissue location. The interplay between nutrients and cytokine signaling (Signal 3) is crucial for coordinating nutrient uptake and metabolic rewiring with T cell fate. Overall, understanding how nutrients regulate T cell immunity in different microenvironments provides insights into adaptive immunity and therapeutic interventions.