These cells recognise peptides presented on HLA class II molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly immunoregulatory functions. They produce cytokines and provide co-stimulatory signals that support the activation of CD8 ⁺ T lymphocytes and assist the production of mature antibody by B cells. In addition, their close interaction with phagocytes determines cytokine production by both cell types. CD4 lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce:

 -  Th1 (T-helper) cells typically produce IL-2, IFN-γ and TNF-α, and support the development of delayed-type hypersensitivity responses.

- Th2 cells typically produce IL-4, IL-5, IL-10 and IL-13, and promote allergic responses.

- T-regulatory cells (T-regs) are a further subset of specialised CD4 ⁺ lymphocytes that are important in actively suppressing activation of other cells and preventing autoimmune disease. They produce cytokines such as TGF-β and IL-10.

- Th17 cells are pro-inflammatory cells defined  by their production of IL-17. They are related to regulatory T cells. Th17 cells have a key role in defense against extracellular bacteria and fungi. They also have a role in the development of autoimmune disease.

 T-cell activation is regulated by a balance between co-stimulatory molecules , the second signal required for activation, and inhibitory molecules that down-regulate T-cell activity. One such inhibitory molecule, CTLA4, has been harnessed therapeutically in the form of abatacept, which is a fusion protein comprised of the Fc fragment of immunoglobulin linked to CTLA4. This is used to inhibit T-cell activation in rheumatoid arthritis and solid organ transplantation.