CD4 T cells are critical components of the adaptive immune system. The T cell receptor (TCR) and co-receptor signaling cascades shape the phenotype and functions of CD4 T cells. TCR signaling plays a crucial role in T cell development, antigen recognition, activation, and differentiation upon recognition of foreign- or auto-antigens. In specific autoimmune conditions, altered TCR repertoire is reported and can predispose autoimmunity with organ-specific inflammation and tissue damage. TCR signaling modulates various signaling cascades and regulates epigenetic and transcriptional regulation during homeostasis and disease conditions. Understanding the mechanism by which coreceptors and cytokine signals control the magnitude of TCR signal amplification will aid in developing therapeutic strategies to treat inflammation and autoimmune diseases. This review focuses on the role of the TCR signaling cascade and its components in the activation, differentiation, and plasticity of various CD4 T cell subsets.