What is the diagnostic significance of CD4/CD8 double-positive T cells?

The majority of naive or reactive T cells seen in bone marrow, peripheral blood, bone marrow, and other tissues express either CD4 (for example, helper or regulatory T cells) or CD8 (for example, cytotoxic T cells). Absence of both CD4 and CD8 can also be seen; for example, gamma-delta T cells often lack expression of both of these antigens. Mature T cells that truly express both CD4 and CD8 (double-positive or DP T cells) are much less common, and thus often raise concern when seen.

During normal development, mostly occurring in the thymus, maturing T cells pass through a CD4/CD8 double-positive phase. This directly precedes final maturation to CD4-positive and CD8-positive naive T cells. Thus, one would expect to encounter cells with a DP phenotype in normal thymus, thymic hyperplasia, and thymoma. Thymic tissue can also occur ectopically in rare circumstances, usually in the neck. The neoplastic correlate of thymus is T lymphoblastic leukemia/lymphoma (T-ALL). Since this is a neoplasm of immature T cells, the DP phenotype is very common in this disease (see Figure 1A). For this reason, when immature DP T cells are seen in mediastinal or cervical masses, care must be taken to distinguish T-ALL from normal maturing thymic T cells. This topic has been covered in a prior Q&A feature.

FIGURE 1: Examples of CD4/CD8 Double-Positive T Cells. Plots show gated T-lineage cells only. Normal T-cell populations are colored green; abnormal/neoplastic populations are red. A. T lymphoblastic leukemia/lymphoma (T-ALL); B. T-cell prolymphocytic leukemia (T-PLL); C. Infiltrating T cells in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).



Amongst mature T-cell neoplasms, the DP phenotype is most commonly seen in T prolymphocytic leukemia (T-PLL). This is an uncommon peripheral T-cell lymphoma that often presents with marked lymphocytosis, hepatosplenomegaly, and lymphoadenopathy. T cells in these specimens express CD2, CD3, and CD7, although CD3 expression may be weak. Most are CD4-positive and CD8-negative, but a significant subset expresses both CD4 and CD8, and is thus a hallmark of this disease (see Figure 1B). The DP phenotype has also been described in peripheral T-cell lymphoma, not otherwise specified, but it is uncommon.

Although the DP phenotype can be a hallmark of lymphoma, caution must be exercised as DP cells can also be seen in the normal T-cell repertoire. This population generally represents a very small fraction of T cells, but it can be expanded in certain reactive conditions. These include autoimmune diseases, such as myasthenia gravis, rheumatoid arthritis, and multiple sclerosis, among others, as well as other chronic inflammatory conditions. In addition, this population has been described in the inflammatory infiltrate of tumors, such as in nodular lymphocyte-predominant Hodgkin lymphoma (see Figure 1C). Another important consideration is artifact. Doublets (two lymphocytes sticking to each other) can appear to be DP T cells, when in fact they are just two cells. So care should be taken to exclude doublets in all cases.

In summary, the discovery of a DP T-cell population in flow cytometry analysis should appropriately raise concern for T-cell neoplasms, including T-ALL and T-PLL. However, because this is a normal T-cell population that is seen during T-cell development or in certain reactive conditions, careful correlation with clinical and morphologic features is required.

References:

Borowitz MJ, Chan JKC (2008) T lymphoblastic leukemia/lymphoma. In SH Swerdlow, E Campo, NL Harris, et al. (eds), WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition. pp. 176-178.

Catovsky D, Muller-Hermelink HK, Ralfkiaer E (2008) T-cell prolymphocytic leukemia. In SH Swerdlow, E Campo, NL Harris, et al. (eds), WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition. pp. 270-271.

Overgaard NH, Jung JW, Steptoe RJ, Wells JW (2015) CD4+/CD8+ double-positive T cells: more than just a developmental stage? J Leukoc Biol. 97:31-38.

Parel Y, Chizzolini C (2004) CD4+ CD8+ double positive T cells in health and disease. Autoimmun Rev. 3:215-220.

Rahemtullah A, Reichard KK, Preffer FI, Harris NL, Hasserjian RP (2006) A double-positive CD4+CD8+ T-cell population is commonly found in nodular lymphocyte predominant Hodgkin lymphoma. Am J Clin Pathol. 126:805-814.