Lymphocyte proliferation as a consequence of molecular mimicry by infectious agents

An increasing number of viruses are known to infect lymphocytes, and directly or indirectly induce lymphocyte proliferation. Both retroviruses and DNA viruses infect lymphocytes. Human GD4 ' T cells are infected by the nontransforming retroviruses human immunodeficiency virus type 1 (HIV-1) and HIV-2 and by the transforming retrovirus human T lympho-tropic virus type I (HTLV-I) while CDS cells are transformed by HTLV-I. Human B cells are infected with two herpesviruses: Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV8). Likewise, human T cells are infected with at least three herpesviruses: HHV6 and HHV7 and herpesvirus saimiri. Mouse B cells are infected with murine mammary tumor virus (MMTV), resulting in augmented T and B cell proliferation. Other organisms have subverted lymphocyte signal transduction pathways for enhanced rep-licative fitness, to impair the host immune response or both. A list of some of these agents and their targets are found in Table 4.

Table 4 Examples of pathogens that can alter lymphocyte prolieration

Organism

Comment

Viruses HIV

HTLV-I, II

Feline leukemia virus (FeLV) Bovine leukemia virus (BLV)

Poxviruses EBV

HHV-6 HHV-7 H. saimiri MMTV Bacteria Staphylococcus

Protozoa Theileria parvum

Infects CD4 cells via CD4 and chemokine coreceptors env gp120 primes uninfected CD4 T cells for antigen-induced apoptosis net p27 perturbs TCR signal transduction, and may predispose thymocytes to negative selection

HIV gag proteins bind to cyclophilins A and B via a cyclosporine-inhibitable interaction, and gag:CyP binding may inhibit T cell activation Vpr gene product arrests infected T cells in the G2+M phase of the cell cycle Transforms T cells. An immunosuppressive peptide homologous to the p15E product of FeLV,

MuLV, and HTLV-I inhibits protein kinase C-dependent responses FeLV-infected lymphocytes have impaired calcium mobilization to a variety of stimuli BLV can transform bovine lymphocytes. The env gene for BLV encodes a TAM motif, and this may induce aberrant or constitutive signal transduction through the Src family of protein tyrosine kinases

Poxviruses produce soluble IL-1 and tumor necrosis factor a (TNFa) binding proteins that inhibit cytokine signals by ligand:receptor competition LMP2A, a transmembrane protein of Epstein-Barr virus, encodes a TAM motif, and signal transduction via the motif may contribute to immortalization of B cells The binding of EBV to the B cell receptor CR2 elevates calcium, and may be involved in the initial infection of B cells. EBV-transformed B cells have impaired antigen receptor-induced calcium mobilization Infects T cells and increases CD4 expression. Transactivates HIV expression. Infects human CD4 cells. Uses CD4 as a receptor Some strains transform human T cells

Infects mouse B cells, and causes superantigen specific T cell proliferation

T cell activation induced by microbial superantigens, and this may induce proliferation or apoptosis of T cells

T. parvum is an intracellular parasite that can transform bovine lymphocytes and causes constitutive IL-2 mRNA expression

From Siegel JN and June CH (1995) Signal transduction and T lymphocyte activation. In: Rich RR (ed) Principles of Clinical Immunology. St Louis, MO: Mosby Year Book.

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