Benefit delayed immunosenescence by regulating CD4+T cells: A promising therapeutic target for aging-related diseases

Abstract

CD4⁺T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4⁺T cells results in a series of changes in the CD4⁺T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4⁺T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4⁺T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4⁺T cell subsets, we reveal the crucial role of CD4⁺T cells in the occurrence and development of age-related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4⁺T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly.

Keywords: Naïve CD4+T cells; aging‐related diseases; effector CD4+T cells; immunosenescence; memory CD4+T cells.

FIGURE 1

The key role of different subtypes of CD4⁺T cells in the immune microenvironment of age‐related diseases. Tregs are stimulated by DCs in age‐related diseases, downregulating the threshold for resistance to exogenous antigens and, in turn, maintaining the tolerant function of DCs. DCs promote CD4⁺Teff differentiation to Tfh by increasing cytokine secretion. Furthermore, IL‐6 secreted by DCs is dependent on enhanced responses of senescent CD4⁺TN. B cells influence CD4⁺Tm differentiation and longevity. MDSCs secrete IL‐10 and arginase products to facilitate the differentiation of Treg. Senescent neutrophils in circulation increase pro‐inflammatory activity and activate Th1 by releasing inflammatory factors during severe infections. The cooperation of MΦ with MDSC and Treg may influence other cells differentiation tendencies. Weakened ability of MΦ‐derived cytokines regulating the microenvironment may lead to immune deficiency of CD4⁺Tm. DCs, Dendritic cells; MΦ, monocyte macrophages; MDSCs, myeloid‐derived suppressor cells. The arrows represent that there are intercellular interactions.

FIGURE 2

Reconfiguration of CD4⁺T cell distribution from bone marrow to peripheral compartments during immunosenescence. Aging leads to a shift in hematopoietic stem cells (HSCs) regulated by mesenchymal stem cells (MSCs), favoring myeloid cell differentiation over lymphoid cell differentiation within the bone marrow and reducing pre‐T output. In the periphery, thymus function declines, resulting in reduced maturation of CD4⁺T cells and impaired self‐renewal capacity. Due to repeated stimulation by internal and external viruses, bacteria, chronic inflammation, etc., there is a withdrawal of CD4⁺TN, differentiation of CD4⁺Teff into Th1, Th2, Th9, Th17, Tfh, and Treg. Additionally, there is an increase in the number of CD4⁺Tm. Replication senescence and impaired apoptosis of CD4⁺Tm lead to the accumulation of CD4⁺TEMRA in the bone marrow and peripherals. ↑, Increase in number; ↓, Decline in number.

FIGURE 3

The crucial role of CD4⁺T cells in age‐related diseases. AD, Alzheimer disease; ALS, Amyotrophic lateral sclerosis; BC, Breast cancer; COVID‐19, Corona virus disease 2019; CVD, Cerebrovascular disease; HIV, Human immunodeficiency virus; ILA, Interstitial lung abnormality; KCS, Malignant keratoconjunctivitis; MS, Multiple sclerosis; OSCC, Oral squamous cells carcinoma; PC, Prostate cancer; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematosus.