Characterization of CD4+ CTLs Ex Vivo

Abstract

The cytotoxic potential of CD8+ T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4+ T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4+ T cells have been the subject of debate. Here we show that a population of CD4+ perforin+ T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4+ T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4+ T cells. The existence of CD4+ cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

Perforin level in CD4+ T cells from patients with systemic lupus erythematosus

“…These cells constitute the subset of CD45R0 + CD27 -activated CD4 + T cells, which are formed during differentiation of naive CD45RA + CCR7 + T cells [42,43]. Therefore, our analysis, conducted on the whole CD4 + T cell population after immune magnetic enrichment, may underestimate PRF1 transcript and protein levels in cytotoxic/effector CD4 + T cells.…”

“…The cytotoxic/effector CD4 + T cells make up a small amount of the whole circulating CD4 + T population [42]. These cells constitute the subset of CD45R0 + CD27 -activated CD4 + T cells, which are formed during differentiation of naive CD45RA + CCR7 + T cells [42,43].…”

“…Despite CD4 + T cells function mainly as helper cells, a, subpopulation of these cells also functions in an effector capacity by carrying out cytotoxicity in a peptide-specific and MHC class II-restricted mode [19]. The latter function of CD4 + T cells mainly depends on granzyme B and perforin-1 (PRF1) exocytosis rather than on CD95-ligand binding to CD95 [19]. An increased presence of cytotoxic CD4 + T cells has been associated with vascular damage and incidence of various autoimmune diseases, including SLE [20][21][22][23][24].…”

Immune surveillance of intracellular pathogens via autophagy

“…Recent evidence, discussed in this review, suggests that cytosolic and nuclear antigens can gain access to MHC class II-loading compartments via autophagy. Thus, autophagic degradation contributes to MHC class II presentation of intracellular antigens to CD4 þ T cells cytotoxic effects on virus-infected cells [85][86][87][88] and contribute to the control of viral infections. [89][90][91][92][93] Given these important roles of CD4 þ T cells for adaptive immunity, it seems crucial that endogenous antigen be presented not only on MHC class I, but also on MHC class II.…”

IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro

“…Th1-type CD4 þ T cells secrete IFN-g and may mediate delayed-type hypersensitivity responses that can lead to enhanced cross-presentation of tumor antigens by host antigen-presenting cells (APCs), 6 and consequent epitope spreading in the evolving antitumor T-cell repertoire. 7,8 Furthermore, CD4 þ T cells may mediate direct tumoricidal activity via tumor necrosis factor (TNF) family ligand members and can inhibit tumor angiogenesis via locoregional production of IFN-g. [9][10][11][12] Antitumor Th1-type CD4 þ T cells, however, appear inhibited in many cancer patients, 5,13,14 as reflected by decreased proliferation and T-cell receptor signaling, 15 as well as by increased frequencies and activity of regulatory T cells. 16,17 Whereas Th1-type responses have been associated with spontaneous or therapy-induced regression of tumor lesions, 14,18 tumor-infiltrating lymphocytes isolated from patients with progressive lesions have been generally reported to exhibit dominant Th2-type (secreting interleukin (IL)-4, IL-5) or regulatory (Th3)-type (secreting IL-10, TGF-b1) responses.…”