Functional dichotomy of CD4⁺ T helper lymphocytes in asymptomatic human immunodeficiency virus infection

Abstract

The majority of asymptomatic, human immune deficiency virus seropositive (HIV+) individuals exhibit a defect in CD4+ T helper cell (Th) function that is selective for responses to recall antigens, but not to HLA alloantigens. The CD4-dependent Th response to HLA alloantigens (Allo) can be mediated by two distinct Th pathways: self-restricted CD4+ Th that recognize allogeneic determinants processed and presented by autologous or self accessory or antigen-presenting cells (sAC); and allo-restricted, CD4+ Th that recognize allogeneic determinants directly on allogeneic accessory or antigen-presenting cells (aAC). In contrast, the Th response to recall antigens requires CD4+ Th and sAC and is therefore limited to the major histocompatibility complex (MHC) self-restricted pathway. Peripheral blood leukocytes from 56 asymptomatic HIV+ patients that exhibited a selective defect in CD4+ Th function were analyzed to determine whether the Th response to Allo was entirely functional, or whether one of the CD4-mediated components of the Allo Th response was also defective. By depletion of AC and/or CD8+ Th subsets (to analyze CD4+ Th function), we demonstrated that HIV+ patients who were selectively deficient in Th function to recall antigens were also unresponsive to Allo presented by autologous AC (HLA self-restricted Th pathway), but retained Allo Th activity presented by allogeneic AC (allo-restricted CD4+ Th pathway). These findings indicate that the CD4+ Th defect seen in the majority of asymptomatic, HIV+ individuals is not limited to recall antigens, but also extends to the component of the response to HLA alloantigens that involves the self-restricted, CD4+ Th pathway. Thus, the Th defect observed in asymptomatic, HIV+ patients does not involve a CD4+ Th defect per se, but is limited to the HLA self-restricted component of Th function.

Spontaneous and antigen-induced production of HIV-inhibitory β-chemokines are associated with AIDS-free status

“…This might indicate that the response to a ''maximal'' and nonspecific stimulus, like PHA, is not as significantly impaired in subjects with AIDS, whereas the loss of response to antigen stimulation occurs earlier on in the course of AIDS. This is consistent with the finding that, as AIDS progresses, a loss of T helper response to antigen stimulation is observed (40)(41)(42) and that, chronologically, loss of response to PHA is the last to occur, being associated with a severe immune dysfunction involving both CD4 ϩ and CD8 ϩ T cells (42). The lack of significance in differences in levels of chemokine production upon PHA stimulation might help to explain why studies by Clerici et al (43) and Mackewicz et al (44) failed to show a beneficial effect of chemokines in AIDS, because their studies used PHA as a stimulus.…”

Human IL-18 Receptor and ST2L Are Stable and Selective Markers for the Respective Type 1 and Type 2 Circulating Lymphocytes

“…AIDS is one human disease in which understanding the role of lymphocyte subsets is critical, but it has remained unclear and controversial. It has been suggested that during HIV infection there is a shift from Th1 to Th2 cell balance accompanying the progression of HIV infection (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, evidence has also been presented that the shift was from Th1 to Th0 phenotype (23).…”

Impaired proliferative capacity and abnormal cytokine profile of naive and memory CD4 T cells from HIV-seropositive patients

“…In addition, the helper activity of CD4 T cells for B cell differentiation and responses to allospecific self-restricted CD4-mediated pathways are defective [12,13], and a decreased IL-2 and interferon-gamma (IFN-y) production has also been reported in a significant proportion of HIV+ asymptomatic subjects [4,9].…”