Lymphocytes

Lymphocytes are central to the adaptive immune system and the defense of the body. There are three major types of lymphocyte. These are natural killer (NK) cells that play a role in innate immunity; T cells that regulate adaptive immunity and are responsible for cell-mediated immune responses; and B cells that are responsible for antibody production. Within these major types are many subpopulations, each with different characteristics and functions. This chapter reviews the structure and properties of these lymphocytes and some important subpopulations.

Lymphocyte Structure

Lymphocytes are small, round cells, 7 to 15 µm in diameter. Each contains a large, round nucleus that stains intensely and evenly with hematoxylin (Figure 13-1). The nucleus is surrounded by a thin rim of cytoplasm containing some mitochondria, free ribosomes, and a small Golgi apparatus (Figure 13-2). Scanning electron microscopy shows that some lymphocytes are smooth surfaced, whereas others are covered by many small projections (Figure 13-3). NK cells are usually larger than T or B cells and may contain obvious cytoplasmic granules. With this exception, lymphocyte structure provides no clue as to their function or complexity (Figure 13-4).

FIGURE 13-1 Photomicrographs showing lymphocytes in stained blood smears from horse, cat, and dog. Giemsa stain. (Courtesy Dr. M.C. Johnson.)

Lymphocyte Populations

Lymphocytes are found throughout the body in lymphoid organs, in blood, and scattered under mucosal surfaces (Figure 13-5). Despite their uniform appearance, they are a diverse mixture of subpopulations. Although these subpopulations cannot be identified by their structure, they can be identified by their characteristic cell surface molecules and by their behavior (Table 13-1). The pattern of cell surface molecules expressed on a cell is called its phenotype. By analyzing cell phenotypes, it is possible to identify many lymphocyte subpopulations.

Table 13-1

Identifying Features of T and B Cells

PROPERTY	B CELLS	T CELLS
Develop within	Bone marrow, bursa, Peyer’s patches	Thymus
Distribution	Lymph node cortex Splenic follicles	Lymph node paracortex Spleen periarteriolar sheath
Circulate	No	Yes
Antigen receptors	BCR—immunoglobulin	TCR—protein heterodimer Associated with CD3, CD4, or CD8
Important surface antigens	Immunoglobulins	CD2, CD3, CD4, or CD8
Mitogens	Pokeweed, lipopolysaccharide	Phytohemagglutinin, concanavalin A, BCG vaccine, pokeweed
Antigens recognized	Free foreign proteins	Processed foreign proteins in MHC antigens
Tolerance induction	Difficult	Easy
Progeny cells	Plasma cells, memory cells	Effector T cells, memory T cells
Secreted products	Immunoglobulins	Cytokines

The loss of cell-mediated immunity as a result of neonatal thymectomy first demonstrated the existence of T lymphocytes (Figure 13-6). After T cells leave the thymus, they accumulate in the paracortex of lymph nodes, the periarteriolar lymphoid sheaths of the spleen, and the interfollicular areas of the Peyer’s patches. T cells also account for 60% to 80% of the lymphocytes in blood (Table 13-2).

Table 13-2

Major Peripheral Blood Lymphocyte Populations in Mammals as Percentages of the Total Population

	T CELLS	B CELLS	CD4+	CD8+	CD4/ CD8
Horses	38-66	17-38^g	56^h	20-37^g	4.75^h
Bovine	45-53^a	16-21^a	8-31	10-30	1.53^a
Sheep	56-64^b	11-50^c	8-22^c	4-22^c	1.55^b
Pigs	45-57^d	13-38^e	23-43	17-39	1.4^f
Dogs	46-72	7-30	27-33ⁱ	17-18ⁱ	1.7ⁱ
Cats	31-89^j	6-50^j	19-49^j	6-39^j	1.9^j
Humans	70-75	10-15	43-48^k	22-24^k	1.9-2.4^k

^a Park YH, Fox LK, Hamilton MJ, Davis WC: Bovine mononuclear leukocyte subpopulations in peripheral blood and mammary gland secretions during lactation, J Dairy Sci 75:998–1006, 1992.

^b Thorp BH, Seneque S, Staute K, Kimpton WG: Characterization and distribution of lymphocyte subsets in sheep hemal nodes, Dev Comp Immunol 15:393–400, 1991.

^c Smith HE, Jacobs RM, Smith C: Flow cytometric analysis of ovine peripheral blood lymphocytes, Can J Vet Res 58:152–155, 1994.

^d Pescovitz MD, Sakopoulos AB, Gaddy JA, et al: Porcine peripheral blood CD4+/CD8+ dual expressing T-cells, Vet Immunol Immunopathol 43:53–62, 1994.

^e Saalmüller A, Bryant J: Characteristics of porcine T lymphocytes and T-cell lines, Vet Immunol Immunopathol 43:45–52, 1994.

^f Joling P, Bianchi AT, Kappe AL, Zwart RJ: Distribution of lymphocyte subpopulations in thymus, spleen, and peripheral blood of specific pathogen free pigs from 1 to 40 weeks of age, Vet Immunol Immunopathol 40:105–118, 1994.

^g McGorum BC, Dixon PM, Halliwell RE: Phenotypic analysis of peripheral blood and bronchoalveolar lavage fluid lymphocytes in control and chronic obstructive pulmonary disease affected horses, before and after “natural (hay and straw) challenges,”Vet Immunol Immunopathol 36:207–222, 1993.

^h Grunig G, Barbis DP, Zhang CH, et al: Correlation between monoclonal antibody reactivity and expression of CD4 and CD8 alpha genes in the horse, Vet Immunol Immunopathol 42:61–69, 1994.

ⁱ Rivas AL, Kimball ES, Quimby FW, Gebhard D: Functional and phenotypic analysis of in vitro stimulated canine peripheral blood mononuclear cells, Vet Immunol Immunopathol 45:55–71, 1995.

^j Walker R, Malik R, Canfield PJ: Analysis of leucocytes and lymphocyte subsets in cats with naturally-occurring cryptococcosis but differing feline immunodeficiency virus status, Aust Vet J 72:93–97, 1995.

^k Bleavins MR, Brott DA, Alvey JD, de la Iglesia FA: Flow cytometric characterization of lymphocyte subpopulations in the cynomolgus monkey (Macaca fascicularis), Vet Immunol Immunopathol 37:1–13, 1993.

NK cells were identified as a result of the presence of cytotoxic activity in lymphocytes from unsensitized animals. NK cells probably originate from the same stem cells as T cells but do not undergo thymic processing. They are widely distributed throughout the lymphoid organs. They account for 5% to 10% of blood lymphocytes.

Lymphocyte Surface Molecules

Many lymphocyte surface molecules have been characterized, especially in humans and mice (Box 13-1). Each molecule usually has a functional or chemical name as well as a cluster of differentiation (CD) designation (Figures 13-7 and 13-8). Currently, the CD nomenclature system gives sequential numbers to each molecule: CD4, CD8, CD16, and so on, up to CD360. Since arbitrary numbers are difficult to remember, the basic principle used in this text is that if the molecule’s common name is well accepted or describes its function, that name will be used. Examples include FcαR (CD89), interleukin-6R (CD126), and L-selectin (CD62L). CD nomenclature is also used for molecules for which the designation is well accepted, such as CD8 and CD4. A list of the most relevant CD molecules and their functions can be found in Appendix 1.

Box 13-1 A Note on Cell Phenotypes

All the cells of the body arise from a single precursor cell, the fertilized ovum. As the embryo develops and grows, cells differentiate both structurally and biochemically. They do this by activating required genes while turning off unneeded ones. One obvious result is that cells acquire a characteristic morphology. Histologic examination shows these structural differences and has provided much useful guidance regarding a cell’s function. Structural differences are limited, however, in what they can tell us. For example, T and B cells look identical but differ significantly in their biochemistry and their function. As a result, biochemical differences must be determined to identify functional cell types. One of the best ways to do this is to examine the proteins expressed on the cell surface. Cells express hundreds of different proteins on their surface, and their identification provides a powerful tool to characterize cells. The CD system of identifying cell surface proteins is an organized attempt to catalog these cell surface proteins.

Two otherwise identical cell populations may be distinguished by the set of cell surface molecules they express. In identifying cells in this way, it is possible not only to identify cell subpopulations but also to follow cell development and differentiation as cells differentiate. Different genes are turned on and off depending on changes in the cell’s function.

In many cases it has proved possible to identify cell subpopulations or changes in a cell’s phenotype without determining the cell’s functional significance. Different phenotypes occur in different domestic animal species. Students will therefore find much of the literature in this area confusing, especially if large numbers of CD molecules are reported for a specific cell phenotype.

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