Table 1 Characteristic features of CD4⁺ CTLs

Surface markers

CD4⁺, CD27/CD28^-, NK-like receptors⁺, CD107a⁺, CRTAM⁺, CX3CR1⁺, CCR7^-, CD62L^-, CD40L^-, ICOS⁺

CD4⁺, CD27/CD28⁺, CD107a^-, CX3CR1^-, CCR7^+/-, CD62L^+/-, CD40L⁺, ICOS^high

CD8⁺, CD27/CD28^+/-, NK-like receptors⁺, CD107a⁺, CRTAM⁺, CCR7^+/-, CD62L^+/-, ICOS^low

^2,52,150

Transcription factors

Runx3^high, ThPOK^low, T-bet⁺, Blimp1⁺, Hobit⁺, Eomes⁺

ThPOK^high, Runx3^low, T-bet⁺ (Th1), GATA3⁺ (Th2), RORγt⁺ (Th17), Bcl6⁺ (Tfh)

Runx3^high, ThPOK^low, T-bet⁺, Blimp1⁺, Eomes⁺

^35,50,57,89

MHC restriction

MHC II restriction

MHC II restriction

MHC I restriction

²

Cytotoxic molecules

Perforin, Granzyme B, FasL, TRAIL

Not typically secreted

Perforin, Granzyme B, FasL, TRAIL

^23,45

Cytotoxic capacity

Moderate cytotoxicity, more sustained, common in chronic diseases or as a complement to CD8+ CTLs’ function

Weak or absent

Strong cytotoxicity, prone to exhaustion in chronic infections or cancer

^4,151

Cytokine profile

IFN-γ, TNF-α, IL-2, M-CSF, GM-CSF

IFN-γ, TNF-α, IL-2 (Th1); IL-4, IL-5, IL-13 (Th2); IL-17 (Th17); IL-4, IL-21 (Tfh)

IFN-γ, TNF-α, IL-2

^142,143

Proliferative potential

Moderate, less robust than CD8⁺ CTLs, but more sustained in chronic responses

High, capable of robust clonal expansion upon antigen stimulation

Strong proliferative burst during acute responses, but susceptible to exhaustion in chronic settings

^2,4

Sensitivity to apoptosis

Low, relatively resistant to apoptosis, especially in chronic inflammation

High, sensitive to activation-induced cell death

High, prone to apoptosis and functional exhaustion under persistent antigen stimulation

¹⁴⁹

Treg suppression sensitivity

Low; relative resistance to Treg-mediated suppression due to CD28 loss and reduced expression of pro-apoptotic molecules

High, readily suppressed by Tregs to maintain immune tolerance

Low, relative resistance to Treg-mediated suppression, with context-dependent modulation

^51,148

Ability to provide help signals to B cells

Limited, linked to CD40L deficiency

Strong, particularly Tfh subset, via IL-21, IL-4, CD40L, essential for germinal center reactions

Minimal, generally lack direct B cell help capacity

³¹