Functional and Clinical Differences Between CD4 and CD8 T Cells
Core Functional Distinction
CD4+ T cells are helper T cells that coordinate immune responses by activating other immune cells, while CD8+ T cells are cytotoxic T lymphocytes that directly kill infected or malignant cells. 1
Molecular Recognition and MHC Interaction
- CD4+ T cells recognize antigens presented on MHC class II molecules, which are expressed on professional antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells 1, 2
- CD8+ T cells recognize antigens presented on MHC class I molecules, which are expressed on virtually all nucleated cells, allowing them to survey for intracellular pathogens or malignant transformation 2, 3
- Both CD4 and CD8 molecules serve as coreceptors that enhance T cell receptor signaling and increase intercellular adhesion during antigen recognition 2
Primary Effector Functions
CD4+ Helper T Cells
- Activate B cells in germinal centers through CD4+ T follicular helper (Tfh) cells, driving conversion into antibody-secreting plasma cells and generating high-affinity antibodies 4
- Secrete cytokines that orchestrate immune responses, including Th2 cytokines that stimulate immunoglobulin production by B cells 1, 4
- Provide "help" for CD8+ CTL differentiation through CD40 signaling on antigen-presenting cells, which is essential for effective CTL priming 3
- Differentiate into multiple subsets (Th1, Th2, Th17, Tregs) based on the local cytokine milieu, each with distinct effector functions 1
CD8+ Cytotoxic T Cells
- Directly kill target cells expressing specific antigens, including virus-infected cells and tumor cells 1, 5
- Express cytotoxic granules containing perforin and granzymes that induce target cell apoptosis 1
- Function as T-suppressor/cytotoxic cells that eliminate cells presenting foreign or aberrant antigens 1
Clinical Significance in Disease States
HIV/AIDS Monitoring
- CD4+ T cell count is the primary marker for immune function assessment in HIV, with critical thresholds: <200 cells/mm³ indicates significant immunosuppression requiring opportunistic infection prophylaxis, <500 cells/mm³ indicates immune compromise, and ≥500 cells/mm³ indicates preserved immune function 6
- The CD4/CD8 ratio provides additional information about immune dysfunction not captured by CD4 count alone and may predict non-AIDS events 6
- CD4 counts should be monitored every 3-6 months in HIV-infected persons to guide antiretroviral therapy and prophylaxis decisions 6
Autoimmune Disease
- Autoreactive CD4+ and CD8+ T cells break self-tolerance to autoantigens when regulatory T cells fail to prevent autoreactivity, as seen in autoimmune hepatitis 1
- CD4+ Th cells present autoantigenic peptides via class II HLA alleles, while CD8+ CTLs recognize peptides via class I HLA alleles 1
Lymphoma Classification
- Most peripheral T-cell lymphomas express CD4 rather than CD8 (CD4>CD8 in PTCL-NOS), though CD4-/CD8+, CD4-/CD8-, and CD4+/CD8+ cases occur 1
- Immunophenotyping must distinguish CD3+CD4+ from CD3+CD8+ populations to properly classify T-cell malignancies 1
Laboratory Reporting Standards
- Report CD4+ T cells as those positive for both CD3 and CD4, not just CD4 alone, to exclude non-T cells from the count 1
- Report CD8+ T cells as those positive for both CD3 and CD8 to ensure accurate identification of T-suppressor/cytotoxic cells 1
- The sum of %CD3+CD4+ and %CD3+CD8+ cells should equal total %CD3+ cells within ±5% (maximum variability ≤10%) as a quality control measure 1
Lineage Plasticity Considerations
- CD4+ T cell lineage identity is not absolutely fixed—under certain physiological conditions, CD4+ T cells can be reprogrammed to express CD8 lineage genes and develop cytotoxic function, particularly in intestinal intraepithelial lymphocytes 7, 5
- CD8 lineage genes are actively repressed in CD4+ T cells by transcription factors like ThPOK and histone deacetylases to maintain helper T cell lineage integrity 7