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Both interferon gamma (IFN-gamma) produced by T helper 1 (TH1) lymphocytes and interleukin-4 (IL-4) produced by TH2 lymphocytes were reduced in either bulk circulating mononuclear cells or mitogen-induced CD4+ T cell clones from the peripheral blood of individuals infected with human immunodeficiency virus (HIV). There was a preferential reduction in clones producing IL-4 and IL-5 in the advanced phases of infection. However, enhanced proportions of CD4+ T cell clones producing both TH1-type and TH2-type cytokines (TH0 clones) were generated from either skin-infiltrating T cells that had been activated in vivo or peripheral blood T cells stimulated by antigen in vitro when cells were isolated from HIV-infected individuals. All TH2 and most TH0 clones supported viral replication, although viral replication was not detected in any of the TH1 clones infected in vitro with HIV. These results suggest that HIV (i) does not induce a definite TH1 to TH2 switch, but can favor a shift to the TH0 phenotype in response to recall antigens, and (ii) preferentially replicates in CD4+ T cells producing TH2-type cytokines (TH2 and TH0).

A large panel of human CD4+ T helper (Th) cell clones with established Th1, Th2, or Th0 profiles of cytokine secretion were examined for the expression of CD30, a member of the tumor necrosis factor receptor superfamily. Th1 clones expressed poor or no CD30 mRNA, and showed low or undetectable expression of both membrane and soluble CD30 (sCD30) protein, whereas Th2 clones showed both CD30 mRNA and membrane CD30 and released substantial amounts of sCD30, Th0 clones exhibited an intermediate pattern of CD30 expression and release. When T cells from the same donor were stimulated with three different antigens (purified protein derivative, PPD; Toxocara canis excretory/secretory antigen, TES; Lalium perenne group I, Lol p I), production of high concentrations of IFN‐γ, but not expression of CD30 or production of IL‐4 and IL‐5, were observed at any time after stimulation with PPD. In contrast, both CD30 expression and production of IL‐4 and IL‐5. but not of IFN‐γ, were concomitantly detectable in TES‐ and Lol p I‐reactive T cells, suggesting a temporal relationship between CD30 expression and beginning of Th2‐typc cytokine production. Finally, CD4+CD30+ T cells specific for Lol p I and inducible to production of Th2‐type cytokines were sorted out from the circulation of grass‐sensitive patients in concomitance with the onset of allergic symptoms during the seasonal exposure to grass pollen. Thus, CD30 expression appears to be associated with the differentiation/activation pathway of human T cells producing Th2‐type cytokines.—Del Prete, G., De Carli, M., Almerigogna, F., Daniel, C. K., D'Elios, M. M., Zancuoghi, G., Virante, F., Pizzolo, G., Romagnani, S. Preferential expression of CD30 by human CD4+ T cells producing Th2‐type cytokines, FASEB J. 9, 81‐86 (1995)

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO ϩ T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects.In conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control. ( J. Clin. Invest. 1996. 98:1185-1194.)

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Helicobacter pylori (Hp) infection almost invariably results in chronic antral gastritis, but only a proportion of patients develop peptic ulcer. Some Hp strains may be more ulcerogenic than others, but some ulcerogenic mechanisms may also depend on the type of the host immune response. In this study, the antigen specificity and the cytokine profile of 53 Hp-specific CD4+ T cell clones derived from the antral mucosa of five patients with Hp-induced uncomplicated chronic gastritis (CG) were assessed and compared with those of 34 Hp-specific CD4+ T cell clones derived from six Hp-infected patients with chronic gastritis and peptic ulcer (CG-PU). The majority (28/34; 82%) of gastric Hp-specific T cell clones from CG-PU patients expressed the Th1 profile and 17 (all Th1) of the 34 clones were specific for cytotoxin-associated protein (CagA). In contrast, 34 (64%) of the 53 Hp-specific gastric T cell clones derived from CG patients were able to secrete both Th1 and Th2 cytokines (Th0 profile) and only 36% expressed a polarized Th1 profile. The majority (85%) of Hp-specific clones from CG patients recognized Hp antigens other than CagA, since 13/53 (25%) were specific for urease, 6 (11%) for VacA, 6 (11%) for HSP and 20 (38%) for other undefined Hp antigens. Results provide evidence that the type of T helper cell response against Hp may vary according to the antigen involved and suggest that a polarized Th1 response may play a role in the genesis of peptic ulcer, whereas a local Th0 response, including interleukin-4 production, may represent an individual host factor which contributes to lower the degree of gastric inflammation and prevent ulcer complication.

Autoimmune gastritis and Helicobacter pylori–associated gastric atrophy develop through similar mechanisms involving the proton pump H+,K+–adenosine triphosphatase as autoantigen. Here, we report that H. pylori–infected patients with gastric autoimmunity harbor in vivo–activated gastric CD4+ T cells that recognize both H+,K+–adenosine triphosphatase and H. pylori antigens. We characterized the submolecular specificity of such gastric T cells and identified cross-reactive epitopes from nine H. pylori proteins. Cross-reactive H. pylori peptides induced T cell proliferation and expression of T helper type 1 functions. We suggest that in genetically susceptible individuals, H. pylori infection can activate cross-reactive gastric T cells leading to gastric autoimmunity via molecular mimicry.